Abuse-deterrent pharmaceutical compositions of opiods and other ...
http://www.pharmcast.com/Patents200/Yr2008/July200 [2008-7-31]
Tag : Zinc Coated
Abstract
An abuse-deterrent pharmaceutical composition has been developed toreduce the likelihood of improper administration of drugs,especially drugs such as opiods. In the preferred embodiment, adrug is modified to increase its lipophilicity. In preferredembodiments the modified drug is homogeneously dispersed withinmicroparticles composed of a material that is either slowly solubleor not soluble in water. In some embodiments the drug containingmicroparticles or drug particles are coated with one or morecoating layers, where at least one coating is water insoluble andpreferably organic solvent insoluble, but enzymatically degradableby enzymes present in the human gastrointestinal tract. Theabuse-deterrent composition retards the release of drug, even ifthe physical integrity of the formulation is compromised (forexample, by chopping with a blade or crushing) and the resultingmaterial is placed in water, snorted, or swallowed. However, whenadministered as directed, the drug is slowly released from thecomposition as the composition is broken down or dissolvedgradually within the GI tract by a combination of enzymaticdegradation, surfactant action of bile acids, and mechanicalerosion.
Description of the Invention
SUMMARY OF THE INVENTION
An abuse-deterrent pharmaceutical composition and the method ofmaking and using the composition have been developed. Thecomposition can be used to reduce the likelihood of improperadministration of drugs, especially drugs such as oxycodone. Thetechnology is useful for a number of other drugs where sustainedrelease oral delivery is desired, and there is the potential forabuse if the drug dose is made immediately available for nasal, IVor oral administration. In the preferred embodiment, the drug ischemically modified to increase its lipophilicity. In otherembodiments, the formulation contains lipophilic or water-insolublematerials or is made using a process which increases thelipophilicity and/or water-insolubility of the composition.
The abuse-deterrent composition retards the release of drug, evenif the physical integrity of the dosage form is compromised (forexample, by chopping with a blade or crushing) and the resultingmaterial is placed in water, snorted, or swallowed. The compositionthus provides a deterrent to common methods of improperadministration including IV injection of drug dissolved in waterand nasal or oral administration of the crushed formulation sincedrug will not be immediately released from the formulation.However, when administered as directed, the drug is slowly released(typically over a period of 4-18 hours) from the composition as thecomposition is broken down or dissolved gradually within the GItract by a combination of enzymatic degradation, surfactant actionof bile acids, and mechanical erosion.
In some embodiments, the individual drug-containing microparticlesor drug particles are coated with one or more independent coatinglayers. At least one of the coating materials is water-insolubleand preferably organic solvent-insoluble, but enzymaticallydegradable. The components of the resulting coated microparticlesare not mutually soluble in water, organic solvents, or anycombination thereof, so that in vitro degradation of theformulation will require more than one step. Hence the drug is noteasily extractable from such a formulation by conventional chemicalmeans. In contrast, when administered to the gastrointestinal tractvia swallowing, the drug gradually will be released from the coatedmicroparticles as a consequence of enzymatic degradation,surfactant action of bile acids and mechanical erosion within theGI tract.
The pharmaceutical composition, when administered orally, resultsin a desired drug release profile. Such a release profile providesa therapeutic effect for an extended period of time, typically from6 to 24 hours. Additional compositions are provided which achieve asmall immediate dose that precedes the sustained release of drug.The compositions disclosed herein may optionally comprise a drughaving no appreciable abuse potential.
DETAILED DESCRIPTION OF THE INVENTION
Disclosed herein are an abuse-deterrent pharmaceutical compositionand the method of making and using the composition.
I. Compositions
As used herein, "composition" refers to the drug dosageunit for administration to a patient. This may also be used inreference solely to the active ingredient, or to the formulationcontaining the active ingredient.
The currently available sustained release dosage forms containingnarcotic analgesics and other drugs are subject to misuse, in part,because mechanical destruction of the dosage form exposes theencapsulated drug and allows for immediate dissolution of the druginto aqueous media. Two properties of the dosage form thatcontribute to this outcome are (1) the ease with which drug isexposed to the extraction media and (2) the high water solubilityof the drug salt form.
In the composition disclosed herein, one or both of theseproperties are altered in order to achieve an abuse-deterrentcomposition. Specifically, in the preferred embodiment, the drug ismodified to increase its lipophilicity and, in additional preferredembodiments, is then homogeneously dispersed within a material thatis either slowly soluble or not soluble in water and subsequentlyformulated into microparticles. The drug may be present in the formof discrete particles or may be partially or fully dispersed in thecarrier material on a molecular level.
The terms "abuse-deterrent composition" or"abuse-deterrent formulation" are used interchangeablyherein to refer to compositions that reduce the potential forimproper administration of drugs but that deliver a therapeuticallyeffective dose when administered as directed. Improperadministration includes tampering with the dosage form and/oradministering the drug by any route other than instructed. Forexample, for a tablet or capsule, methods of tampering with thedosage form may include, but are not limited to, breaking,crushing, grinding, chewing and/or dissolving the tablet or thecontents of the capsule. For oral administration, improperadministration includes administering the drug by any route otherthan via swallowing.
The abuse deterrent composition preferably comprises a drugmodified to increase its lipophilicity. In other preferredembodiments, the drug is homogenously dispersed withinmicroparticles composed of a material that is either slowly solublein water or water insoluble. The compositions slow the release ofdrug if the dosage form is chopped or crushed and the resultingmaterial is placed in water, snorted, or swallowed since most ofthe drug will remain associated with or entrapped within portionsof the core material of the microparticles. In some embodiments thedrug containing microparticles or individual drug particles arecoated with one or more coating layers, where at least one coatingis water insoluble and preferably organic solvent insoluble, butenzymatically degradable. The components of the resulting coatedmicroparticles are not mutually soluble in water, organic solvents,or any combination thereof, such that no one solvent or enzymesolution is capable of dissolving the formulation in its entiretyin vitro. It follows that extraction of the drug from theformulation cannot be carried out in one step. However, whenadministered as directed, the drug is slowly released from theformulation since it is eroded within the environment of thegastrointestinal tract.
A. Drugs to be Formulated
There are many drugs that it is desirable to deliver using thecompositions described herein. The Controlled Substances Act (CSA),Title II of the Comprehensive Drug Abuse Prevention and Control Actof 1970, places all substances that are regulated under existingfederal law into one of five schedules based upon the substance'smedicinal value, harmfulness, and potential for abuse or addiction.Drugs that are preferred include those classified as Schedule II,III, IV and V drugs. Drugs that are most preferable include those,like oxycodone, that are currently formulated as sustained orcontrolled release compositions, where drug release is intended tooccur over a prolonged period of time through the gastrointestinaltract, and immediate or burst release, for example, by inhalationor injection, is undesirable. As used herein, drugs prone to abuserefer to controlled substance specified as schedule II, III, IV andV drugs.
The terms "drug", "active agent", and"pharmacologically active agent" are used interchangeablyherein to refer to a chemical compound that induces a desiredpharmacological, physiological effect. The terms also encompasspharmaceutically acceptable derivatives of those active agentsspecifically mentioned herein, including, but not limited to,salts, solvates, hydrates, complexes with one or more molecules,prodrugs, active metabolites, analogs, and the like. When the terms"active agent", "pharmacologically activeagent" and "drug" are used, or when a particulardrug, such as oxycodone, is identified, it is to be understood asincluding the active agent per se as well as pharmaceuticallyacceptable salts, solvates, hydrates, complexes with one or moremolecules, prodrugs, active metabolites, and analogs.
Examples of preferred drugs include, 1-phenylcyclohexylamine,1-piperidinocyclohexanecarbonitrile, alfentanil,alphacetylmethadol, alphaprodine, alprazolam, amobarbital,amphetamine, anileridine, apomorphine, aprobarbital, barbital,barbituric acid derivative, bemidone, benzoylecgonine,benzphetamine, betacetylmethadol, betaprodine, bezitramide,bromazepam, buprenorphine, butabarbital, butalbital, butorphanol,camazepam, cathine, chloral, chlordiazepoxide, clobazam,clonazepam, clorazepate, clotiazepam, cloxazolam, cocaine, codeine,chlorphentermine, delorazepam, dexfenfluramine, dextromoramide,dextropropoxyphen, dezocine, diazepam, diethylpropion, difenoxin,dihydrocodeine, dihydromorphine, dioxaphentyl butyrate, dipanone,diphenoxylate, diprenorphine, ecgonine, enadoline, eptazocine,estazolam, ethoheptazine, ethyl loflazepate, ethylmorphine,etorphine, femproponex, fencamfamin, fenfluramine, fentanyl,fludiazepam, flunitrazepam, flurazepam, glutethimide, halazepam,haloxazolam, hexalgon, hydrocodone, hydromorphone, isomethadone,hydrocodone, ketamine, ketazolam, ketobemidone, levanone,levoalphacetylmethadol, levomethadone, levomethadyl acetate,levomethorphan, levorphanol, lofentanil, loperamide, loprazolam,lorazepam, lormetazepam, lysergic acid, lysergic acid amide,mazindol, medazepam, mefenorex, meperidine, meptazinol, metazocine,methadone, methamphetamine, methohexital, methotrimeprazine,methyldihydromorphinone, methylphenidate, methylphenobarbital,metopon, morphine, nabilone, nalbuphine, nalbupine, nalorphine,narceine, nefopam, nicomorphine, nimetazepam, nitrazepam,nordiazepam, normethadone, normorphine, oxazepam, oxazolam,oxycodone, oxymorphone, pentazocine, pentobarbital, phenadoxone,phenazocine, phencyclidine, phendimetrazine, phenmetrazine,pheneridine, piminodine, prodilidine, properidine, propoxyphene,racemethorphan, racemorphan, racemoramide, remifentanil,secobarbital, sufentanil, talbutal, thebaine, thiamylal,thiopental, tramadol, trimeperidine, and vinbarbital.
In addition to the compounds above, the following scheduled drugsmay be incorporated into the composition: allobarbitone,alprazolam, amylobarbitone, aprobarbital, barbital, barbitone,benzphetamnine, brallobarbital, bromazepam, brotizolam, buspirone,butalbital, butobarbitone, butorphanol, camazepam, captodiame,carbromal, carfentanil, carpipramine, cathine, chloral, chloralbetaine, chloral hydrate, chloralose, chlordiazepoxide,chlorhexadol, chlormethiazole edisylate, chlormezanone,cinolazepam, clobazam, potassium clorazepate, clotiazepam,cloxazolam, cyclobarbitone, delorazepam, dexfenfluramine, diazepam,diethylpropion, difebarbamate, difenoxin, enciprazine, estazolam,ethyl loflazepate, etizolam, febarbamate, fencamfamin,fenfluramine, fenproporex, fluanisone, fludiazepam, flunitraam,flunitrazepam, flurazepam, flutoprazepam, gepirone, glutethimide,halazepam, haloxazolam, hexobarbitone, ibomal, ipsapirone,ketazolam, loprazolam mesylate, lorazepam, lormetazepam, mazindol,mebutamate, medazepam, mefenorex, mephobarbital, meprobamate,metaclazepam, methaqualone, methohexital, methylpentynol,methylphenobarbital, midazolam, milazolam, morphine, nimetazepam,nitrazepam, nordiazepam, oxazepam, oxazolam, paraldehyde, pemoline,pentabarbitone, pentazocine, pentobarbital, phencyclidine,phenobarbital, phendimetrazine, phenmetrazine, phenprobamate,phentermine, phenyacetone, pinazepam, pipradol, prazepam,proxibarbal, quazepam, quinalbaritone, secobarbital,secbutobarbitone, sibutramine, temazepam, tetrazepam, triazolam,triclofos, zalepan, zaleplon, zolazepam, zolpidem, and zopiclone.Certain compounds described herein may exist in particulargeometric or stereoisomeric forms. The composition disclosed hereincontemplates all such compounds, including cis- and trans-isomers,R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, theracemic mixtures thereof, compounds of different spacialconformations, and other mixtures thereof, as falling within thescope of the invention. Additional asymmetric carbon atoms may bepresent in a substituent such as an alkyl group. All such isomers,as well as mixtures thereof, are intended to be included in thisinvention.
As used herein, "pharmaceutically acceptable salts" referto derivatives of the disclosed compounds wherein the parentcompound is modified by making acid or base salts thereof. Examplesof pharmaceutically acceptable salts include, but are not limitedto, mineral or organic acid salts of basic residues such as amines;alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts includethe conventional non-toxic salts or the quaternary ammonium saltsof the parent compound formed, for example, from non-toxicinorganic or organic acids. For example, such conventionalnon-toxic salts include those derived from inorganic acids such ashydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitricand the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic,tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic,phenylacetic, glutamic, benzoic, salicylic, sulfanilic,2-acetoxybenzoic, fumaric, tolunesulfonic, methanesulfonic, ethanedisulfonic, oxalic, and isethionic.
The pharmaceutically acceptable salts of the compounds can besynthesized from the parent compound, which contains a basic oracidic moiety, by conventional chemical methods. Generally, suchsalts can be prepared by reacting the free acid or base forms ofthese compounds with a stoichiometric amount of the appropriatebase or acid in water or in an organic solvent, or in a mixture ofthe two; generally, non-aqueous media like ether, ethyl acetate,ethanol, isopropanol, or acetonitrile are preferred. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences,20th ed., Lippincott Williams & Wilkins, Baltimore, Md., 2000,p. 704, the disclosure of which is hereby incorporated byreference.
Optionally, the composition described herein can further include adrug having no appreciable abuse potential.
B. Drug Solubility Modification
In preferred embodiments, the solubility characteristics of a drugare altered prior to incorporation into the formulation.Modification of the drug to produce a more lipophilic derivativeserves to reduce the water solubility of the drug and thus reducesthe aqueous extractability. Furthermore, if the drug is made morelipophilic, it can be solubilized in a molten fatty substance orwax like mixture, rather than physically dispersed in a particulateform. Solubilization of drug enhances the abuse-deterrentproperties of microparticles formulated from the mixture as it isdifficult to extract drug from an intimately dispersed composition.
The terms "lipophilic derivative" and "lipophililicdrug derivative", as used herein, refer to derivatives of thedrug that are less soluble in water than the most soluble salt ofthe drug. The most soluble salt being selected from either drugalkaline metal salts (for acidic drugs) or salts of the drug withinorganic acids (for basic drugs). The examples of the latterinclude but are not limited to hydrohalates, sulfates, andnitrates.
Some of the methods that can be used to alter the drug'slipophilicity are outlined below. It is understood that two or moreapproaches can be combined to achieve a desired solubility profile.
Methods for Increasing Lipophilicity
In one embodiment, drug is made more lipophilic by eliminating orreducing the overall charge of the drug molecule. For example, fora basic drug, a water soluble salt (such as hydrochloride, sulfate,or maleate) can be converted to a free base using techniques knownin the art. Correspondingly, in the case of an acidic drug, a watersoluble salt (such sodium, potassium, or the like) can be convertedto a free acid.
In another embodiment, the drug's lipophilicity is increased byforming a salt between a drug molecule and a charged lipophiliccompound. In this case the lipophilicity of the resulting salt canbe manipulated by varying the lipophilicity of the counter-ion. Ingeneral lipophilic acids or amines with chain lengths betweenC.sub.5-C.sub.30 are lipophilic counter-ion candidates. Somespecific examples include, but are not limited to, linoleic acid,octanoic acid, lauric acid, stearic acid, palmitic acid, oleicacid, octyl amine, lauryl amine, stearyl amine, palmityl amine,linoleyl amine, and oleyl amine. Other salts which may increaselipophilicity and, hence, lipid solubility relative to the parentdrug compound include, but are not limited to, pectinate, tannate,phytate, salicylate, saccharinate, acesulfamate, gallate, andterephthalate salts.
In yet another embodiment the lipophilicity of the drug isincreased by fanning a stable complex between a drug molecule(either charged or uncharged) and a metal cation such as zinc,magnesium, calcium, bismuth or the like. This complex may consistof one or more drug molecules, one or more metal cations, and,optionally, one or more lipophilic charged species. Theaforementioned charged lipophilic species are incorporated into thecomplex if necessary to bring the charge of the final complex tozero and increase its overall lipophilicity. In general lipophilicacids or amines with chain lengths between C.sub.5-C.sub.30 arelipophilic counter-ion candidates.
In still a further embodiment, drug lipophilicity is increased viacomplexation with poorly water-soluble cyclodextrin. For example,ethylated beta-cyclodextrin has been shown to decrease aqueoussolubility of complexed drug molecules.
In another embodiment, a drug is covalently modified to increaseits lipophilicity. For example, a lipophilic compound can becovalently attached to a drug molecule via an ester or amidelinkage. Such drug derivatives are cleaved in vivo, thus releasingthe parent compound.
C. Drug Containing Microparticles
In preferred embodiments, drugs are formulated with a carriermaterial to form microparticles. As used herein, the term"microparticle" refers to a composition comprising a drugdispersed within a carrier material and "coatedmicroparticle" refers to a composition comprising a drugcontaining microparticle or a drug particle coated with one or morecoating layers of material. Microparticles and coatedmicroparticles have a size range of 10 to 3000 microns in diameter.
Within microparticles, drug is preferably homogeneously dispersedin the form of fine particles within the carrier material. Morepreferably, drug is partially solubilized in molten carriermaterial or partially dissolved with the carrier material in amutual solvent during the formulation of the microparticles. Mostpreferably, drug is completely solubilized in the molten carriermaterial or completely dissolved with the carrier material in aco-solvent during the formulation of the microparticles. This isaccomplished through the selection of materials and the manner inwhich they are processed.
Carrier materials appropriate for the fabrication of drugcontaining microparticles are either slowly soluble in water orinsoluble in water, but capable of degrading within the GI tract bymeans including enzymatic degradation, surfactant action of bileacids and mechanical erosion. As used herein, the term "slowlysoluble in water" refers to materials that are not dissolvedin water within a period of 30 minutes. Preferred examples includefats, fatty substances, waxes, wax-like substances and mixturesthereof. Suitable fats and fatty substances include fatty alcohols(such as lauryl, myristyl stearyl, cetyl or cetostearyl alcohol),fatty acids and derivatives, including but not limited to fattyacid esters, fatty acid glycerides (mono-, di- and tri-glycerides),and hydrogenated fats. Specific examples include, but are notlimited to hydrogenated vegetable oil, hydrogenated cottonseed oil,hydrogenated castor oil, hydrogenated oils available under thetrade name Sterotex.RTM., stearic acid, cocoa butter, and stearylalcohol. Suitable waxes and wax-like materials include natural orsynthetic waxes, hydrocarbons, and normal waxes. Specific examplesof waxes include beeswax, glycowax, castor wax, carnauba wax,paraffins and candelilla wax. As used herein, a wax-like materialis defined as any material which is normally solid at roomtemperature and has a melting point of from about 30 to 300.degree.C.
In some cases, it may be desirable to alter the rate of waterpenetration into the hydrophobic drug containing microparticles. Tothis end, rate-controlling (wicking) agents may be formulated alongwith the fats or waxes listed above. Examples of rate-controllingmaterials include certain starch derivatives (eg, waxy maltodextrinand drum dried corn starch), cellulose derivatives (eg,hydroxypropylmethylcellulose, hydroxypropylcellulose,methylcellulose, and carboxymethylcellulose), alginic acid, lactoseand talc. Additionally, a pharmaceutically acceptable surfactant(for example, lecithin) may be added to facilitate the degradationof such microparticles.
Proteins which are water insoluble, such as zein, are preferredcarrier materials for the formation of drug containingmicroparticles. Additionally, proteins, polysaccharides andcombinations thereof which are water soluble can be formulated withdrug into microparticles and subsequently cross-linked to form aninsoluble network. For example, cyclodextrins can be complexed withindividual drug molecules and subsequently cross-linked.
Certain polymers may also be used as carrier materials in theformulation of drug containing microparticles. Suitable polymersinclude ethylcellulose and other natural or synthetic cellulosederivatives. Polymers which are slowly soluble and form a gel in anaqueous environment, such as hydroxypropyl methylcellulose orpolyethylene oxide may also be suitable as carrier materials fordrug containing microparticles.
Encapsulation or incorporation of drug into carrier materials toproduce drug containing microparticles can be achieved throughknown pharmaceutical formulation techniques. To create acomposition that protects drug from exposure upon mechanicaldisruption (eg, grinding, chewing, or chopping), the drug isintimately dispersed within the carrier material. In the case offormulation in fats, waxes or wax-like materials, the carriermaterial is heated above its melting temperature and the drug isadded to form a mixture comprising drug particles suspended in thecarrier material, drug dissolved in the carrier material, or amixture thereof. Microparticles can be subsequently formulatedthrough several methods including, but not limited to, theprocesses of congealing, extrusion, spray chilling or aqueousdispersion. In a preferred process, wax is heated above its meltingtemperature, drug is added, and the molten wax-drug mixture iscongealed under constant stirring as the mixture cools.Alternatively, the molten wax-drug mixture can be extruded andspheronized to form pellets or beads. Detailed descriptions ofthese processes can be found in "Remington--The science andpractice of pharmacy", 20.sup.th Edition, Jennaro et. Al.,(Phila, Lippencott, Williams, and Wilkens, 2000).
For some carrier materials it may be desirable to use a solventevaporation technique to produce drug containing microparticles. Inthis case drug and carrier material are co-dissolved in a mutualsolvent and microparticles can subsequently be produced by severaltechniques including, but not limited to, forming an emulsion inwater or other appropriate media, spray drying or by evaporatingoff the solvent from the bulk solution and milling the resultingmaterial.
In addition to modification of the drug itself, processingconditions can be used to influence the dispersion of the drugwithin water-insoluble or slowly water soluble material. Forexample, in the case where the water in-soluble or slowly solublematerial is melted and drug is fully or partially dissolved understirring conditions, the temperature, agitation rate and time ofprocessing will influence the degree of dissolution achieved. Morespecifically, a more homogenous dispersion may be achieved with ahigher temperature, faster stirring rate and longer processingtime. Ultrasound can also be applied to the molten mixture toincrease the degree of dispersion and/or the rate of dissolution ofthe drug.
In some embodiments, drug in a particulate form is homogeneouslydispersed in a water-insoluble or slowly water soluble material. Tominimize the size of the drug particles within the composition, thedrug powder itself may be milled to generate fine particles priorto formulation. The process of jet milling, known in thepharmaceutical art, can be used for this purpose. In someembodiments drug in a particulate form is homogeneously dispersedin a wax or wax like substance by heating the wax or wax likesubstance above its melting point and adding the drug particleswhile stirring the mixture. In this case a pharmaceuticallyacceptable surfactant may be added to the mixture to facilitate thedispersion of the drug particles.
D. Coated Drug Containing Microparticles
In some embodiments, drug containing microparticles or drugparticles are encapsulated within at least one water-insolubleenzymatically degradable material. In some instances the substratesof digestive enzymes are naturally water-insoluble and can beutilized in the formulation without further processing. Solidesters of fatty acids, which are hydrolyzed by lipases, can bespray coated onto microparticles or drug particles. Zein is anexample of a naturally water-insoluble protein. It can be coatedonto drug containing microparticles or drug particles by spraycoating or by wet granulation techniques. In addition to naturallywater-insoluble materials, some substrates of digestive enzymes canbe treated with cross-linking procedures, resulting in theformation of non-soluble networks. Many methods of cross-linkingproteins, initiated by both chemical and physical means, have beenreported. One of the most common methods to obtain cross-linking isthe use of chemical cross-linking agents. Examples of chemicalcross-linking agents include aldehydes (gluteraldehyde andformaldehyde), epoxy compounds, carbodiimides, and genipin. Inaddition to these cross-linking agents, oxidized and native sugarshave been used to cross-link gelatin (Cortesi, R., et al.,Biomaterials 19 (1998) 1641-1649). Cross-linking can also beaccomplished using enzymatic means; for example, transglutaminasehas been approved as a GRAS substance for cross-linking seafoodproducts. Finally, cross-linking can be initiated by physical meanssuch as thermal treatment, UV irradiation and gamma irradiation.
To produce a coating layer of cross-linked protein surrounding drugcontaining microparticles or drug particles, a water solubleprotein can be spray coated onto the microparticles andsubsequently cross-linked by the one of the methods describedabove. Alternatively, drug containing microparticles can bemicroencapsulated within protein by coacervation-phase separation(for example, by the addition of salts) and subsequentlycross-linked. Some suitable proteins for this purpose includegelatin, albumin, casein, and gluten.
Polysaccharides can also be cross-linked to form a water-insolublenetwork. For many polysaccharides, this can be accomplished byreaction with calcium salts or multivalent cations which cross-linkthe main polymer chains. Pectin, alginate, dextran, amylose andguar gum are subject to cross-linking in the presence ofmultivalent cations. Complexes between oppositely chargedpolysaccharides can also be formed; pectin and chitosan, forexample, can be complexed via electrostatic interactions. Insolublecoatings can be formed on particles in this fashion. It should benoted that in many cases polysaccharides are broken downspecifically by enzymes produced by bacteria within the colon.
In some cases a water-insoluble but enzymatically degradablecoating comprising both a protein and a polysaccharide can beproduced if the components are oppositely charged polyelectrolytes.Under the proper temperature, pH, and concentrations, the twopolymers can interact through their opposite electrical charges andform a water-insoluble complex. If a core particle is present atthe time the complex phase separates, it will be coated. Forexample, gelatin and gum arabic can be coated onto a core particleutilizing this process. Optionally, the complex can be madeirreversibly insoluble by subsequent cross-linking induced bychemical or physical means.
E. Dosage Forms
There are a number of drug compositions that meet the abusedeterrent criteria outlined above. In one embodiment a drug ishomogeneously dispersed, in a fine particulate form, within awater-insoluble or slowly water soluble material and the mixture isformulated into microparticles. In another embodiment a drug ispartially dissolved within a water-insoluble or slowly watersoluble material during the manufacturing process, for example, bymixing at a temperature above the melting point of the carriermaterial, and the mixture is formulated into microparticles. In yetanother embodiment a drug is fully dissolved within awater-insoluble or slowly water soluble material during themanufacturing process, for example, by mixing at a temperatureabove the melting point of the carrier material, and the mixture isformulated into microparticles. In still a further embodiment, thedrug containing microparticles, where the drug is homogeneouslydispersed in a particulate form, or has been partially or fullydissolved within the carrier material during the manufacturingprocess, are coated with one or more coatings to form coatedmicroparticles. In a further embodiment, drug particles are coateddirectly with one or more coatings to form coated microparticles.
The microparticles, coated microparticles, or a mixture thereof areformed into a solid dosage form suitable for oral administration.For example, microparticles or coated microparticles can beincorporated into hard capsules, dispersed within a soft gelatincapsule, or combined with appropriate excipients and tableted bycompression.
In some embodiments, the compositions are coated with an entericcoating. Enteric coatings known in the art are applied directly tothe abuse-deterrent microparticle or coated microparticlecompositions or are applied to the surface of a capsule or tabletcomprising the abuse deterrent microparticle and/or coatedmicroparticle compositions. Enteric coatings known in the artinclude, for example, acrylic polymers that are commerciallyavailable under the trade name EUDRAGIT.RTM., cellulose acetatephthalate, hydroxypropylmethylcellulose phthalate, polyvinylacetatephthalate, shellac, hydroxypropylmethylcellulose succinate,cellulose acetate trimelliate or mixtures thereof.
Dosage forms can include one or more drugs. When the dosage formincludes two or more drugs they can be Scheduled drugs or can be acombination of Scheduled and non-Scheduled drugs. The drugs can beincorporated into separate microparticle compositions where theScheduled drugs are incorporated into abuse deterrent microparticlecompositions and the non-Scheduled drugs are incorporated intoabuse deterrent microparticle compostions, sustained releasecompositions known in the art or immediate release compositionsknown in the art. The compositions comprising the different drugsare formulated into a single solid dosage form suitable for oraladministration, for example, they can be incorporated into agelatin capsule, or combined with appropriate excipients andcompressed into a tablet form. Examples of non-scheduled drugs thatmay be included in dosage forms described herein include, but arenot limited to, aspirin, acetaminophen, non-steroidalanti-inflammatory drugs, cyclooxygenase II inhibitors,N-methyl-D-aspartate receptor antagonists, glycine receptorantagonists, triptans, dextromethorphan, promethazine, fiorinal,guaifenesin, butalbital, and caffeine.
An immediate release dose can be incorporated into the formulationin several ways. Immediate release microparticles can be madeutilizing standard methodologies and formulated along withabuse-deterrent microparticle and/or coated microparticlecompositions in a suitable oral dosage form. Alternatively, acoating containing drug which is available for immediate releasecan be placed on a tablet comprising abuse-deterrent microparticleand/or coated microparticle compositions plus appropriateexcipients. Additionally, an immediate dose of drug can begranulated or blended with rapidly dissolving excipients andsubsequently compressed (1) as one layer of bi-layer tablets inwhich the abuse-deterrent microparticle and/or coated microparticlecompositions are compressed as the other layer, or (2) as the outerlayer of compression-coated tablets in which the abuse-deterrentmicroparticle and/or coated microparticle compositions arecompressed as the inner core, or (3) into tablets in whichabuse-deterrent microparticle and/or coated microparticlecompositions are embedded.
In some embodiments, the immediate release portion of the dosageform comprises a lipophilic drug derivative. For example, saltderivatives or complexes that are insoluble at a neutral pH butdissociate, thereby releasing the parent compound, at an acidic pHare ideal for immediate release within the stomach. In the case ofoxycodone some salts tat may exhibit this property include, but arenot limited to, the tannate, phthalate, salicylate, gallate,pectinate, phytate, saccharinate, asesulfamate and terephthalatesalts. Complexes of drug with one or more metal ions and,optionally, one or more lipophilic counter-ions may also be usedfor immediate drug release. Use of salts or complexes in theimmediate release portion of the dosage form reduces the abusepotential of the immediate release dose if the formulation iscrushed and (1) snorted or (2) dissolved in water since these saltswill be poorly soluble under these conditions. It is understood bythe one of ordinary skill in the art that such salts or complexesmay also be used to formulate an immediate release dosage formwithout a sustained release portion.
Additional mechanisms to reduce the potential for abuse can also beincorporated during the process of formulating tablets. Forexample, ingredients can be added to deter chewing or snorting ofthe final formulation. For example, an intensely bitter substancemay deter chewing, while an intensely spicy ingredient, such ascapsaicin, may deter snorting. The addition of a colored dye, whichwould stain the skin and mucosal surface of the nose followingsnorting may also serve to reduce this practice.
Optional excipients present in the oral dosage form comprisingabuse deterrent microparticles or coated microparticles include,but are not limited to diluents, binders, lubricants,disintigrants, colorants, plasticizers and the like. Diluents, alsotermed "fillers," are typically necessary to increase thebulk of a solid dosage form so that a practical size is providedfor compression of tablets. Examples of diluents include cellulose,dry starch, microcrystalline cellulose, dicalcium phosphate,calcium sulfate, sodium chloride confectioner's sugar, compressiblesugar, dextrates, dextrin, dextrose, sucrose, mannitol, powderedcellulose, sorbitol, and lactose. Binders are used to impartcohesive qualities powdered materials and can include materialssuch as starch, gelatin, sugars, natural and synthetic gums,polyethylene glycol, ethylcellulose, methylcellulose,hydroxypropylmethylcellulose, carboxymethylcellulose, waxes andpolyvinyl pyrrolidone. Lubricants are used to facilitate tabletmanufacture; examples of lubricants include talc, magnesiumstearate, calcium stearate, hydrogenated vegetable oils stearicacid, sodium stearyl fumarate, sodium benzoate, sodium acetate,leucine, sodium oleate, sodium lauryl sulfate, magnesium laurylsulfate and polyethylene glycol. Disintegrants can be added topharmaceutical formulations in order to facilitate"breakup" or disintegration after administration.Materials used for this purpose include starches, clays,celluloses, aligns, gums, and cross-linked polymers. A plasticizermay be included in coating materials to alter their mechanicalproperties. Examples of plasticizers include benzyl benzoate,chlorobutanol, dibutyl sebacate, diethyl phthalate, glycerin,mineral oil, polyethylene glycol, sorbitol, triacetin, triethylcitrate, glycerol, etc. In addition to the additives above,coloring and flavoring agents may also be incorporated into thecomposition.
Optionally, the composition disclosed herein comprises materialswherein a combination of the materials is not soluble in water,organic solvent, or any combination thereof.
II. Methods of Administration
It is assumed that upon oral ingestion of the intact composition,drug is released as the formulation is gradually broken down ordissolved within the GI tract by a combination of enzymaticdegradation, surfactant action of bile acids, and mechanicalerosion. This is a result of the unique ability of the humandigestive system to efficiently break down or solubilize a varietyof materials. The process within the GI tract that results in thedigestion of food and the absorption of nutrients is well known.Following mastication within the mouth, food passes into thestomach where it is mixed with digestive juices. This fluidcontains the proteolytic enzyme pepsin which, following activationby the low pH within the stomach, begins the process of cleavingingested proteins into smaller peptide fragments. Food then entersthe small intestine in the form of macromolecular aggregates, whereit is digested into molecules near or in a form capable of beingabsorbed. This digestion is accomplished through the action ofvarious enzymes which are produced in the pancreas and flow intothe upper portion of the large intestine, the duodenum. The enzymessynthesized in the pancreas include proteases, amylases andlipases; these enzymes are capable of breaking down proteins,starches and fats, respectively. The digestion of fats is furtherfacilitated by the secretion of bile into the duodenum since bilesalts, which contain both hydrophobic and hydrophilic portions, arecapable of emulsifying lipids into minute droplets in order toincrease the surface area available for digestion by lipases. Thematerial which remains following passage through the smallintestine enters the large intestine. Bacteria capable of breakingdown carbohydrates not digested in the small intestine (such ascellulose) are present in large numbers this region of thedigestive tract. Finally, in addition to microbial fermentation,the large intestine functions to absorb water and electrolytes andto form and store feces until they are excreted.
In addition to providing a deterrent to common methods ofabuse/diversion, the formulation can provide a sustained release ofdrug over an extended time period. This is a natural consequence ofthe fact that, in the present formulation, drug is slowly releasedfrom a predominantly water-insoluble, hydrophobic matrix followingthe degradation of the matrix. The barrier components are degraded,for example, by enzymes, the surfactant action of bile acids andmechanical erosion.
In some embodiments, an immediate release of drug is achievedwithin the stomach in order to provide rapid therapeutic onset.
The pharmaceutical drug composition is administered orally. Theappropriate dosage formulations can be obtained by calculation ofthe pharmacokinetics of the formulation, then adjusting usingroutine techniques to yield the appropriate drug levels based onthe approved dosage forms. Any suitable amount of drug containingmicroparticles or coated microparticles can be included in thefinal formulation. The selection of a suitable amount of drugcontaining microparticles depends on the dosage desired and isreadily determined by those skilled in the art.
In addition to oral administration, some embodiments may also beadministered by other routes, including, but not limited to, rectaland nasal administration. Some embodiments may also be suitable forformulation as oral liquids.
Claim 1 of 30 Claims
1. An orally administrable abuse-deterrent pharmaceuticalcomposition comprising a therapeutically effective amount ofmicroparticles consisting of (a) a lipophilic drug prone to abuseor lipophilic derivative of a drug prone to abuse, and (b) one ormore carrier materials selected from the group consisting of fats,fatty substances, waxes, wax-like substances and mixtures thereof,wherein the drug is dispersed within the one or more carriermaterials, and the release of a portion of incorporated drug isretarded when the physical integrity of the composition iscompromised and the compromised composition is exposed to water.
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Abstract
An abuse-deterrent pharmaceutical composition has been developed toreduce the likelihood of improper administration of drugs,especially drugs such as opiods. In the preferred embodiment, adrug is modified to increase its lipophilicity. In preferredembodiments the modified drug is homogeneously dispersed withinmicroparticles composed of a material that is either slowly solubleor not soluble in water. In some embodiments the drug containingmicroparticles or drug particles are coated with one or morecoating layers, where at least one coating is water insoluble andpreferably organic solvent insoluble, but enzymatically degradableby enzymes present in the human gastrointestinal tract. Theabuse-deterrent composition retards the release of drug, even ifthe physical integrity of the formulation is compromised (forexample, by chopping with a blade or crushing) and the resultingmaterial is placed in water, snorted, or swallowed. However, whenadministered as directed, the drug is slowly released from thecomposition as the composition is broken down or dissolvedgradually within the GI tract by a combination of enzymaticdegradation, surfactant action of bile acids, and mechanicalerosion.
Description of the Invention
SUMMARY OF THE INVENTION
An abuse-deterrent pharmaceutical composition and the method ofmaking and using the composition have been developed. Thecomposition can be used to reduce the likelihood of improperadministration of drugs, especially drugs such as oxycodone. Thetechnology is useful for a number of other drugs where sustainedrelease oral delivery is desired, and there is the potential forabuse if the drug dose is made immediately available for nasal, IVor oral administration. In the preferred embodiment, the drug ischemically modified to increase its lipophilicity. In otherembodiments, the formulation contains lipophilic or water-insolublematerials or is made using a process which increases thelipophilicity and/or water-insolubility of the composition.
The abuse-deterrent composition retards the release of drug, evenif the physical integrity of the dosage form is compromised (forexample, by chopping with a blade or crushing) and the resultingmaterial is placed in water, snorted, or swallowed. The compositionthus provides a deterrent to common methods of improperadministration including IV injection of drug dissolved in waterand nasal or oral administration of the crushed formulation sincedrug will not be immediately released from the formulation.However, when administered as directed, the drug is slowly released(typically over a period of 4-18 hours) from the composition as thecomposition is broken down or dissolved gradually within the GItract by a combination of enzymatic degradation, surfactant actionof bile acids, and mechanical erosion.
In some embodiments, the individual drug-containing microparticlesor drug particles are coated with one or more independent coatinglayers. At least one of the coating materials is water-insolubleand preferably organic solvent-insoluble, but enzymaticallydegradable. The components of the resulting coated microparticlesare not mutually soluble in water, organic solvents, or anycombination thereof, so that in vitro degradation of theformulation will require more than one step. Hence the drug is noteasily extractable from such a formulation by conventional chemicalmeans. In contrast, when administered to the gastrointestinal tractvia swallowing, the drug gradually will be released from the coatedmicroparticles as a consequence of enzymatic degradation,surfactant action of bile acids and mechanical erosion within theGI tract.
The pharmaceutical composition, when administered orally, resultsin a desired drug release profile. Such a release profile providesa therapeutic effect for an extended period of time, typically from6 to 24 hours. Additional compositions are provided which achieve asmall immediate dose that precedes the sustained release of drug.The compositions disclosed herein may optionally comprise a drughaving no appreciable abuse potential.
DETAILED DESCRIPTION OF THE INVENTION
Disclosed herein are an abuse-deterrent pharmaceutical compositionand the method of making and using the composition.
I. Compositions
As used herein, "composition" refers to the drug dosageunit for administration to a patient. This may also be used inreference solely to the active ingredient, or to the formulationcontaining the active ingredient.
The currently available sustained release dosage forms containingnarcotic analgesics and other drugs are subject to misuse, in part,because mechanical destruction of the dosage form exposes theencapsulated drug and allows for immediate dissolution of the druginto aqueous media. Two properties of the dosage form thatcontribute to this outcome are (1) the ease with which drug isexposed to the extraction media and (2) the high water solubilityof the drug salt form.
In the composition disclosed herein, one or both of theseproperties are altered in order to achieve an abuse-deterrentcomposition. Specifically, in the preferred embodiment, the drug ismodified to increase its lipophilicity and, in additional preferredembodiments, is then homogeneously dispersed within a material thatis either slowly soluble or not soluble in water and subsequentlyformulated into microparticles. The drug may be present in the formof discrete particles or may be partially or fully dispersed in thecarrier material on a molecular level.
The terms "abuse-deterrent composition" or"abuse-deterrent formulation" are used interchangeablyherein to refer to compositions that reduce the potential forimproper administration of drugs but that deliver a therapeuticallyeffective dose when administered as directed. Improperadministration includes tampering with the dosage form and/oradministering the drug by any route other than instructed. Forexample, for a tablet or capsule, methods of tampering with thedosage form may include, but are not limited to, breaking,crushing, grinding, chewing and/or dissolving the tablet or thecontents of the capsule. For oral administration, improperadministration includes administering the drug by any route otherthan via swallowing.
The abuse deterrent composition preferably comprises a drugmodified to increase its lipophilicity. In other preferredembodiments, the drug is homogenously dispersed withinmicroparticles composed of a material that is either slowly solublein water or water insoluble. The compositions slow the release ofdrug if the dosage form is chopped or crushed and the resultingmaterial is placed in water, snorted, or swallowed since most ofthe drug will remain associated with or entrapped within portionsof the core material of the microparticles. In some embodiments thedrug containing microparticles or individual drug particles arecoated with one or more coating layers, where at least one coatingis water insoluble and preferably organic solvent insoluble, butenzymatically degradable. The components of the resulting coatedmicroparticles are not mutually soluble in water, organic solvents,or any combination thereof, such that no one solvent or enzymesolution is capable of dissolving the formulation in its entiretyin vitro. It follows that extraction of the drug from theformulation cannot be carried out in one step. However, whenadministered as directed, the drug is slowly released from theformulation since it is eroded within the environment of thegastrointestinal tract.
A. Drugs to be Formulated
There are many drugs that it is desirable to deliver using thecompositions described herein. The Controlled Substances Act (CSA),Title II of the Comprehensive Drug Abuse Prevention and Control Actof 1970, places all substances that are regulated under existingfederal law into one of five schedules based upon the substance'smedicinal value, harmfulness, and potential for abuse or addiction.Drugs that are preferred include those classified as Schedule II,III, IV and V drugs. Drugs that are most preferable include those,like oxycodone, that are currently formulated as sustained orcontrolled release compositions, where drug release is intended tooccur over a prolonged period of time through the gastrointestinaltract, and immediate or burst release, for example, by inhalationor injection, is undesirable. As used herein, drugs prone to abuserefer to controlled substance specified as schedule II, III, IV andV drugs.
The terms "drug", "active agent", and"pharmacologically active agent" are used interchangeablyherein to refer to a chemical compound that induces a desiredpharmacological, physiological effect. The terms also encompasspharmaceutically acceptable derivatives of those active agentsspecifically mentioned herein, including, but not limited to,salts, solvates, hydrates, complexes with one or more molecules,prodrugs, active metabolites, analogs, and the like. When the terms"active agent", "pharmacologically activeagent" and "drug" are used, or when a particulardrug, such as oxycodone, is identified, it is to be understood asincluding the active agent per se as well as pharmaceuticallyacceptable salts, solvates, hydrates, complexes with one or moremolecules, prodrugs, active metabolites, and analogs.
Examples of preferred drugs include, 1-phenylcyclohexylamine,1-piperidinocyclohexanecarbonitrile, alfentanil,alphacetylmethadol, alphaprodine, alprazolam, amobarbital,amphetamine, anileridine, apomorphine, aprobarbital, barbital,barbituric acid derivative, bemidone, benzoylecgonine,benzphetamine, betacetylmethadol, betaprodine, bezitramide,bromazepam, buprenorphine, butabarbital, butalbital, butorphanol,camazepam, cathine, chloral, chlordiazepoxide, clobazam,clonazepam, clorazepate, clotiazepam, cloxazolam, cocaine, codeine,chlorphentermine, delorazepam, dexfenfluramine, dextromoramide,dextropropoxyphen, dezocine, diazepam, diethylpropion, difenoxin,dihydrocodeine, dihydromorphine, dioxaphentyl butyrate, dipanone,diphenoxylate, diprenorphine, ecgonine, enadoline, eptazocine,estazolam, ethoheptazine, ethyl loflazepate, ethylmorphine,etorphine, femproponex, fencamfamin, fenfluramine, fentanyl,fludiazepam, flunitrazepam, flurazepam, glutethimide, halazepam,haloxazolam, hexalgon, hydrocodone, hydromorphone, isomethadone,hydrocodone, ketamine, ketazolam, ketobemidone, levanone,levoalphacetylmethadol, levomethadone, levomethadyl acetate,levomethorphan, levorphanol, lofentanil, loperamide, loprazolam,lorazepam, lormetazepam, lysergic acid, lysergic acid amide,mazindol, medazepam, mefenorex, meperidine, meptazinol, metazocine,methadone, methamphetamine, methohexital, methotrimeprazine,methyldihydromorphinone, methylphenidate, methylphenobarbital,metopon, morphine, nabilone, nalbuphine, nalbupine, nalorphine,narceine, nefopam, nicomorphine, nimetazepam, nitrazepam,nordiazepam, normethadone, normorphine, oxazepam, oxazolam,oxycodone, oxymorphone, pentazocine, pentobarbital, phenadoxone,phenazocine, phencyclidine, phendimetrazine, phenmetrazine,pheneridine, piminodine, prodilidine, properidine, propoxyphene,racemethorphan, racemorphan, racemoramide, remifentanil,secobarbital, sufentanil, talbutal, thebaine, thiamylal,thiopental, tramadol, trimeperidine, and vinbarbital.
In addition to the compounds above, the following scheduled drugsmay be incorporated into the composition: allobarbitone,alprazolam, amylobarbitone, aprobarbital, barbital, barbitone,benzphetamnine, brallobarbital, bromazepam, brotizolam, buspirone,butalbital, butobarbitone, butorphanol, camazepam, captodiame,carbromal, carfentanil, carpipramine, cathine, chloral, chloralbetaine, chloral hydrate, chloralose, chlordiazepoxide,chlorhexadol, chlormethiazole edisylate, chlormezanone,cinolazepam, clobazam, potassium clorazepate, clotiazepam,cloxazolam, cyclobarbitone, delorazepam, dexfenfluramine, diazepam,diethylpropion, difebarbamate, difenoxin, enciprazine, estazolam,ethyl loflazepate, etizolam, febarbamate, fencamfamin,fenfluramine, fenproporex, fluanisone, fludiazepam, flunitraam,flunitrazepam, flurazepam, flutoprazepam, gepirone, glutethimide,halazepam, haloxazolam, hexobarbitone, ibomal, ipsapirone,ketazolam, loprazolam mesylate, lorazepam, lormetazepam, mazindol,mebutamate, medazepam, mefenorex, mephobarbital, meprobamate,metaclazepam, methaqualone, methohexital, methylpentynol,methylphenobarbital, midazolam, milazolam, morphine, nimetazepam,nitrazepam, nordiazepam, oxazepam, oxazolam, paraldehyde, pemoline,pentabarbitone, pentazocine, pentobarbital, phencyclidine,phenobarbital, phendimetrazine, phenmetrazine, phenprobamate,phentermine, phenyacetone, pinazepam, pipradol, prazepam,proxibarbal, quazepam, quinalbaritone, secobarbital,secbutobarbitone, sibutramine, temazepam, tetrazepam, triazolam,triclofos, zalepan, zaleplon, zolazepam, zolpidem, and zopiclone.Certain compounds described herein may exist in particulargeometric or stereoisomeric forms. The composition disclosed hereincontemplates all such compounds, including cis- and trans-isomers,R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, theracemic mixtures thereof, compounds of different spacialconformations, and other mixtures thereof, as falling within thescope of the invention. Additional asymmetric carbon atoms may bepresent in a substituent such as an alkyl group. All such isomers,as well as mixtures thereof, are intended to be included in thisinvention.
As used herein, "pharmaceutically acceptable salts" referto derivatives of the disclosed compounds wherein the parentcompound is modified by making acid or base salts thereof. Examplesof pharmaceutically acceptable salts include, but are not limitedto, mineral or organic acid salts of basic residues such as amines;alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts includethe conventional non-toxic salts or the quaternary ammonium saltsof the parent compound formed, for example, from non-toxicinorganic or organic acids. For example, such conventionalnon-toxic salts include those derived from inorganic acids such ashydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitricand the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic,tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic,phenylacetic, glutamic, benzoic, salicylic, sulfanilic,2-acetoxybenzoic, fumaric, tolunesulfonic, methanesulfonic, ethanedisulfonic, oxalic, and isethionic.
The pharmaceutically acceptable salts of the compounds can besynthesized from the parent compound, which contains a basic oracidic moiety, by conventional chemical methods. Generally, suchsalts can be prepared by reacting the free acid or base forms ofthese compounds with a stoichiometric amount of the appropriatebase or acid in water or in an organic solvent, or in a mixture ofthe two; generally, non-aqueous media like ether, ethyl acetate,ethanol, isopropanol, or acetonitrile are preferred. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences,20th ed., Lippincott Williams & Wilkins, Baltimore, Md., 2000,p. 704, the disclosure of which is hereby incorporated byreference.
Optionally, the composition described herein can further include adrug having no appreciable abuse potential.
B. Drug Solubility Modification
In preferred embodiments, the solubility characteristics of a drugare altered prior to incorporation into the formulation.Modification of the drug to produce a more lipophilic derivativeserves to reduce the water solubility of the drug and thus reducesthe aqueous extractability. Furthermore, if the drug is made morelipophilic, it can be solubilized in a molten fatty substance orwax like mixture, rather than physically dispersed in a particulateform. Solubilization of drug enhances the abuse-deterrentproperties of microparticles formulated from the mixture as it isdifficult to extract drug from an intimately dispersed composition.
The terms "lipophilic derivative" and "lipophililicdrug derivative", as used herein, refer to derivatives of thedrug that are less soluble in water than the most soluble salt ofthe drug. The most soluble salt being selected from either drugalkaline metal salts (for acidic drugs) or salts of the drug withinorganic acids (for basic drugs). The examples of the latterinclude but are not limited to hydrohalates, sulfates, andnitrates.
Some of the methods that can be used to alter the drug'slipophilicity are outlined below. It is understood that two or moreapproaches can be combined to achieve a desired solubility profile.
Methods for Increasing Lipophilicity
In one embodiment, drug is made more lipophilic by eliminating orreducing the overall charge of the drug molecule. For example, fora basic drug, a water soluble salt (such as hydrochloride, sulfate,or maleate) can be converted to a free base using techniques knownin the art. Correspondingly, in the case of an acidic drug, a watersoluble salt (such sodium, potassium, or the like) can be convertedto a free acid.
In another embodiment, the drug's lipophilicity is increased byforming a salt between a drug molecule and a charged lipophiliccompound. In this case the lipophilicity of the resulting salt canbe manipulated by varying the lipophilicity of the counter-ion. Ingeneral lipophilic acids or amines with chain lengths betweenC.sub.5-C.sub.30 are lipophilic counter-ion candidates. Somespecific examples include, but are not limited to, linoleic acid,octanoic acid, lauric acid, stearic acid, palmitic acid, oleicacid, octyl amine, lauryl amine, stearyl amine, palmityl amine,linoleyl amine, and oleyl amine. Other salts which may increaselipophilicity and, hence, lipid solubility relative to the parentdrug compound include, but are not limited to, pectinate, tannate,phytate, salicylate, saccharinate, acesulfamate, gallate, andterephthalate salts.
In yet another embodiment the lipophilicity of the drug isincreased by fanning a stable complex between a drug molecule(either charged or uncharged) and a metal cation such as zinc,magnesium, calcium, bismuth or the like. This complex may consistof one or more drug molecules, one or more metal cations, and,optionally, one or more lipophilic charged species. Theaforementioned charged lipophilic species are incorporated into thecomplex if necessary to bring the charge of the final complex tozero and increase its overall lipophilicity. In general lipophilicacids or amines with chain lengths between C.sub.5-C.sub.30 arelipophilic counter-ion candidates.
In still a further embodiment, drug lipophilicity is increased viacomplexation with poorly water-soluble cyclodextrin. For example,ethylated beta-cyclodextrin has been shown to decrease aqueoussolubility of complexed drug molecules.
In another embodiment, a drug is covalently modified to increaseits lipophilicity. For example, a lipophilic compound can becovalently attached to a drug molecule via an ester or amidelinkage. Such drug derivatives are cleaved in vivo, thus releasingthe parent compound.
C. Drug Containing Microparticles
In preferred embodiments, drugs are formulated with a carriermaterial to form microparticles. As used herein, the term"microparticle" refers to a composition comprising a drugdispersed within a carrier material and "coatedmicroparticle" refers to a composition comprising a drugcontaining microparticle or a drug particle coated with one or morecoating layers of material. Microparticles and coatedmicroparticles have a size range of 10 to 3000 microns in diameter.
Within microparticles, drug is preferably homogeneously dispersedin the form of fine particles within the carrier material. Morepreferably, drug is partially solubilized in molten carriermaterial or partially dissolved with the carrier material in amutual solvent during the formulation of the microparticles. Mostpreferably, drug is completely solubilized in the molten carriermaterial or completely dissolved with the carrier material in aco-solvent during the formulation of the microparticles. This isaccomplished through the selection of materials and the manner inwhich they are processed.
Carrier materials appropriate for the fabrication of drugcontaining microparticles are either slowly soluble in water orinsoluble in water, but capable of degrading within the GI tract bymeans including enzymatic degradation, surfactant action of bileacids and mechanical erosion. As used herein, the term "slowlysoluble in water" refers to materials that are not dissolvedin water within a period of 30 minutes. Preferred examples includefats, fatty substances, waxes, wax-like substances and mixturesthereof. Suitable fats and fatty substances include fatty alcohols(such as lauryl, myristyl stearyl, cetyl or cetostearyl alcohol),fatty acids and derivatives, including but not limited to fattyacid esters, fatty acid glycerides (mono-, di- and tri-glycerides),and hydrogenated fats. Specific examples include, but are notlimited to hydrogenated vegetable oil, hydrogenated cottonseed oil,hydrogenated castor oil, hydrogenated oils available under thetrade name Sterotex.RTM., stearic acid, cocoa butter, and stearylalcohol. Suitable waxes and wax-like materials include natural orsynthetic waxes, hydrocarbons, and normal waxes. Specific examplesof waxes include beeswax, glycowax, castor wax, carnauba wax,paraffins and candelilla wax. As used herein, a wax-like materialis defined as any material which is normally solid at roomtemperature and has a melting point of from about 30 to 300.degree.C.
In some cases, it may be desirable to alter the rate of waterpenetration into the hydrophobic drug containing microparticles. Tothis end, rate-controlling (wicking) agents may be formulated alongwith the fats or waxes listed above. Examples of rate-controllingmaterials include certain starch derivatives (eg, waxy maltodextrinand drum dried corn starch), cellulose derivatives (eg,hydroxypropylmethylcellulose, hydroxypropylcellulose,methylcellulose, and carboxymethylcellulose), alginic acid, lactoseand talc. Additionally, a pharmaceutically acceptable surfactant(for example, lecithin) may be added to facilitate the degradationof such microparticles.
Proteins which are water insoluble, such as zein, are preferredcarrier materials for the formation of drug containingmicroparticles. Additionally, proteins, polysaccharides andcombinations thereof which are water soluble can be formulated withdrug into microparticles and subsequently cross-linked to form aninsoluble network. For example, cyclodextrins can be complexed withindividual drug molecules and subsequently cross-linked.
Certain polymers may also be used as carrier materials in theformulation of drug containing microparticles. Suitable polymersinclude ethylcellulose and other natural or synthetic cellulosederivatives. Polymers which are slowly soluble and form a gel in anaqueous environment, such as hydroxypropyl methylcellulose orpolyethylene oxide may also be suitable as carrier materials fordrug containing microparticles.
Encapsulation or incorporation of drug into carrier materials toproduce drug containing microparticles can be achieved throughknown pharmaceutical formulation techniques. To create acomposition that protects drug from exposure upon mechanicaldisruption (eg, grinding, chewing, or chopping), the drug isintimately dispersed within the carrier material. In the case offormulation in fats, waxes or wax-like materials, the carriermaterial is heated above its melting temperature and the drug isadded to form a mixture comprising drug particles suspended in thecarrier material, drug dissolved in the carrier material, or amixture thereof. Microparticles can be subsequently formulatedthrough several methods including, but not limited to, theprocesses of congealing, extrusion, spray chilling or aqueousdispersion. In a preferred process, wax is heated above its meltingtemperature, drug is added, and the molten wax-drug mixture iscongealed under constant stirring as the mixture cools.Alternatively, the molten wax-drug mixture can be extruded andspheronized to form pellets or beads. Detailed descriptions ofthese processes can be found in "Remington--The science andpractice of pharmacy", 20.sup.th Edition, Jennaro et. Al.,(Phila, Lippencott, Williams, and Wilkens, 2000).
For some carrier materials it may be desirable to use a solventevaporation technique to produce drug containing microparticles. Inthis case drug and carrier material are co-dissolved in a mutualsolvent and microparticles can subsequently be produced by severaltechniques including, but not limited to, forming an emulsion inwater or other appropriate media, spray drying or by evaporatingoff the solvent from the bulk solution and milling the resultingmaterial.
In addition to modification of the drug itself, processingconditions can be used to influence the dispersion of the drugwithin water-insoluble or slowly water soluble material. Forexample, in the case where the water in-soluble or slowly solublematerial is melted and drug is fully or partially dissolved understirring conditions, the temperature, agitation rate and time ofprocessing will influence the degree of dissolution achieved. Morespecifically, a more homogenous dispersion may be achieved with ahigher temperature, faster stirring rate and longer processingtime. Ultrasound can also be applied to the molten mixture toincrease the degree of dispersion and/or the rate of dissolution ofthe drug.
In some embodiments, drug in a particulate form is homogeneouslydispersed in a water-insoluble or slowly water soluble material. Tominimize the size of the drug particles within the composition, thedrug powder itself may be milled to generate fine particles priorto formulation. The process of jet milling, known in thepharmaceutical art, can be used for this purpose. In someembodiments drug in a particulate form is homogeneously dispersedin a wax or wax like substance by heating the wax or wax likesubstance above its melting point and adding the drug particleswhile stirring the mixture. In this case a pharmaceuticallyacceptable surfactant may be added to the mixture to facilitate thedispersion of the drug particles.
D. Coated Drug Containing Microparticles
In some embodiments, drug containing microparticles or drugparticles are encapsulated within at least one water-insolubleenzymatically degradable material. In some instances the substratesof digestive enzymes are naturally water-insoluble and can beutilized in the formulation without further processing. Solidesters of fatty acids, which are hydrolyzed by lipases, can bespray coated onto microparticles or drug particles. Zein is anexample of a naturally water-insoluble protein. It can be coatedonto drug containing microparticles or drug particles by spraycoating or by wet granulation techniques. In addition to naturallywater-insoluble materials, some substrates of digestive enzymes canbe treated with cross-linking procedures, resulting in theformation of non-soluble networks. Many methods of cross-linkingproteins, initiated by both chemical and physical means, have beenreported. One of the most common methods to obtain cross-linking isthe use of chemical cross-linking agents. Examples of chemicalcross-linking agents include aldehydes (gluteraldehyde andformaldehyde), epoxy compounds, carbodiimides, and genipin. Inaddition to these cross-linking agents, oxidized and native sugarshave been used to cross-link gelatin (Cortesi, R., et al.,Biomaterials 19 (1998) 1641-1649). Cross-linking can also beaccomplished using enzymatic means; for example, transglutaminasehas been approved as a GRAS substance for cross-linking seafoodproducts. Finally, cross-linking can be initiated by physical meanssuch as thermal treatment, UV irradiation and gamma irradiation.
To produce a coating layer of cross-linked protein surrounding drugcontaining microparticles or drug particles, a water solubleprotein can be spray coated onto the microparticles andsubsequently cross-linked by the one of the methods describedabove. Alternatively, drug containing microparticles can bemicroencapsulated within protein by coacervation-phase separation(for example, by the addition of salts) and subsequentlycross-linked. Some suitable proteins for this purpose includegelatin, albumin, casein, and gluten.
Polysaccharides can also be cross-linked to form a water-insolublenetwork. For many polysaccharides, this can be accomplished byreaction with calcium salts or multivalent cations which cross-linkthe main polymer chains. Pectin, alginate, dextran, amylose andguar gum are subject to cross-linking in the presence ofmultivalent cations. Complexes between oppositely chargedpolysaccharides can also be formed; pectin and chitosan, forexample, can be complexed via electrostatic interactions. Insolublecoatings can be formed on particles in this fashion. It should benoted that in many cases polysaccharides are broken downspecifically by enzymes produced by bacteria within the colon.
In some cases a water-insoluble but enzymatically degradablecoating comprising both a protein and a polysaccharide can beproduced if the components are oppositely charged polyelectrolytes.Under the proper temperature, pH, and concentrations, the twopolymers can interact through their opposite electrical charges andform a water-insoluble complex. If a core particle is present atthe time the complex phase separates, it will be coated. Forexample, gelatin and gum arabic can be coated onto a core particleutilizing this process. Optionally, the complex can be madeirreversibly insoluble by subsequent cross-linking induced bychemical or physical means.
E. Dosage Forms
There are a number of drug compositions that meet the abusedeterrent criteria outlined above. In one embodiment a drug ishomogeneously dispersed, in a fine particulate form, within awater-insoluble or slowly water soluble material and the mixture isformulated into microparticles. In another embodiment a drug ispartially dissolved within a water-insoluble or slowly watersoluble material during the manufacturing process, for example, bymixing at a temperature above the melting point of the carriermaterial, and the mixture is formulated into microparticles. In yetanother embodiment a drug is fully dissolved within awater-insoluble or slowly water soluble material during themanufacturing process, for example, by mixing at a temperatureabove the melting point of the carrier material, and the mixture isformulated into microparticles. In still a further embodiment, thedrug containing microparticles, where the drug is homogeneouslydispersed in a particulate form, or has been partially or fullydissolved within the carrier material during the manufacturingprocess, are coated with one or more coatings to form coatedmicroparticles. In a further embodiment, drug particles are coateddirectly with one or more coatings to form coated microparticles.
The microparticles, coated microparticles, or a mixture thereof areformed into a solid dosage form suitable for oral administration.For example, microparticles or coated microparticles can beincorporated into hard capsules, dispersed within a soft gelatincapsule, or combined with appropriate excipients and tableted bycompression.
In some embodiments, the compositions are coated with an entericcoating. Enteric coatings known in the art are applied directly tothe abuse-deterrent microparticle or coated microparticlecompositions or are applied to the surface of a capsule or tabletcomprising the abuse deterrent microparticle and/or coatedmicroparticle compositions. Enteric coatings known in the artinclude, for example, acrylic polymers that are commerciallyavailable under the trade name EUDRAGIT.RTM., cellulose acetatephthalate, hydroxypropylmethylcellulose phthalate, polyvinylacetatephthalate, shellac, hydroxypropylmethylcellulose succinate,cellulose acetate trimelliate or mixtures thereof.
Dosage forms can include one or more drugs. When the dosage formincludes two or more drugs they can be Scheduled drugs or can be acombination of Scheduled and non-Scheduled drugs. The drugs can beincorporated into separate microparticle compositions where theScheduled drugs are incorporated into abuse deterrent microparticlecompositions and the non-Scheduled drugs are incorporated intoabuse deterrent microparticle compostions, sustained releasecompositions known in the art or immediate release compositionsknown in the art. The compositions comprising the different drugsare formulated into a single solid dosage form suitable for oraladministration, for example, they can be incorporated into agelatin capsule, or combined with appropriate excipients andcompressed into a tablet form. Examples of non-scheduled drugs thatmay be included in dosage forms described herein include, but arenot limited to, aspirin, acetaminophen, non-steroidalanti-inflammatory drugs, cyclooxygenase II inhibitors,N-methyl-D-aspartate receptor antagonists, glycine receptorantagonists, triptans, dextromethorphan, promethazine, fiorinal,guaifenesin, butalbital, and caffeine.
An immediate release dose can be incorporated into the formulationin several ways. Immediate release microparticles can be madeutilizing standard methodologies and formulated along withabuse-deterrent microparticle and/or coated microparticlecompositions in a suitable oral dosage form. Alternatively, acoating containing drug which is available for immediate releasecan be placed on a tablet comprising abuse-deterrent microparticleand/or coated microparticle compositions plus appropriateexcipients. Additionally, an immediate dose of drug can begranulated or blended with rapidly dissolving excipients andsubsequently compressed (1) as one layer of bi-layer tablets inwhich the abuse-deterrent microparticle and/or coated microparticlecompositions are compressed as the other layer, or (2) as the outerlayer of compression-coated tablets in which the abuse-deterrentmicroparticle and/or coated microparticle compositions arecompressed as the inner core, or (3) into tablets in whichabuse-deterrent microparticle and/or coated microparticlecompositions are embedded.
In some embodiments, the immediate release portion of the dosageform comprises a lipophilic drug derivative. For example, saltderivatives or complexes that are insoluble at a neutral pH butdissociate, thereby releasing the parent compound, at an acidic pHare ideal for immediate release within the stomach. In the case ofoxycodone some salts tat may exhibit this property include, but arenot limited to, the tannate, phthalate, salicylate, gallate,pectinate, phytate, saccharinate, asesulfamate and terephthalatesalts. Complexes of drug with one or more metal ions and,optionally, one or more lipophilic counter-ions may also be usedfor immediate drug release. Use of salts or complexes in theimmediate release portion of the dosage form reduces the abusepotential of the immediate release dose if the formulation iscrushed and (1) snorted or (2) dissolved in water since these saltswill be poorly soluble under these conditions. It is understood bythe one of ordinary skill in the art that such salts or complexesmay also be used to formulate an immediate release dosage formwithout a sustained release portion.
Additional mechanisms to reduce the potential for abuse can also beincorporated during the process of formulating tablets. Forexample, ingredients can be added to deter chewing or snorting ofthe final formulation. For example, an intensely bitter substancemay deter chewing, while an intensely spicy ingredient, such ascapsaicin, may deter snorting. The addition of a colored dye, whichwould stain the skin and mucosal surface of the nose followingsnorting may also serve to reduce this practice.
Optional excipients present in the oral dosage form comprisingabuse deterrent microparticles or coated microparticles include,but are not limited to diluents, binders, lubricants,disintigrants, colorants, plasticizers and the like. Diluents, alsotermed "fillers," are typically necessary to increase thebulk of a solid dosage form so that a practical size is providedfor compression of tablets. Examples of diluents include cellulose,dry starch, microcrystalline cellulose, dicalcium phosphate,calcium sulfate, sodium chloride confectioner's sugar, compressiblesugar, dextrates, dextrin, dextrose, sucrose, mannitol, powderedcellulose, sorbitol, and lactose. Binders are used to impartcohesive qualities powdered materials and can include materialssuch as starch, gelatin, sugars, natural and synthetic gums,polyethylene glycol, ethylcellulose, methylcellulose,hydroxypropylmethylcellulose, carboxymethylcellulose, waxes andpolyvinyl pyrrolidone. Lubricants are used to facilitate tabletmanufacture; examples of lubricants include talc, magnesiumstearate, calcium stearate, hydrogenated vegetable oils stearicacid, sodium stearyl fumarate, sodium benzoate, sodium acetate,leucine, sodium oleate, sodium lauryl sulfate, magnesium laurylsulfate and polyethylene glycol. Disintegrants can be added topharmaceutical formulations in order to facilitate"breakup" or disintegration after administration.Materials used for this purpose include starches, clays,celluloses, aligns, gums, and cross-linked polymers. A plasticizermay be included in coating materials to alter their mechanicalproperties. Examples of plasticizers include benzyl benzoate,chlorobutanol, dibutyl sebacate, diethyl phthalate, glycerin,mineral oil, polyethylene glycol, sorbitol, triacetin, triethylcitrate, glycerol, etc. In addition to the additives above,coloring and flavoring agents may also be incorporated into thecomposition.
Optionally, the composition disclosed herein comprises materialswherein a combination of the materials is not soluble in water,organic solvent, or any combination thereof.
II. Methods of Administration
It is assumed that upon oral ingestion of the intact composition,drug is released as the formulation is gradually broken down ordissolved within the GI tract by a combination of enzymaticdegradation, surfactant action of bile acids, and mechanicalerosion. This is a result of the unique ability of the humandigestive system to efficiently break down or solubilize a varietyof materials. The process within the GI tract that results in thedigestion of food and the absorption of nutrients is well known.Following mastication within the mouth, food passes into thestomach where it is mixed with digestive juices. This fluidcontains the proteolytic enzyme pepsin which, following activationby the low pH within the stomach, begins the process of cleavingingested proteins into smaller peptide fragments. Food then entersthe small intestine in the form of macromolecular aggregates, whereit is digested into molecules near or in a form capable of beingabsorbed. This digestion is accomplished through the action ofvarious enzymes which are produced in the pancreas and flow intothe upper portion of the large intestine, the duodenum. The enzymessynthesized in the pancreas include proteases, amylases andlipases; these enzymes are capable of breaking down proteins,starches and fats, respectively. The digestion of fats is furtherfacilitated by the secretion of bile into the duodenum since bilesalts, which contain both hydrophobic and hydrophilic portions, arecapable of emulsifying lipids into minute droplets in order toincrease the surface area available for digestion by lipases. Thematerial which remains following passage through the smallintestine enters the large intestine. Bacteria capable of breakingdown carbohydrates not digested in the small intestine (such ascellulose) are present in large numbers this region of thedigestive tract. Finally, in addition to microbial fermentation,the large intestine functions to absorb water and electrolytes andto form and store feces until they are excreted.
In addition to providing a deterrent to common methods ofabuse/diversion, the formulation can provide a sustained release ofdrug over an extended time period. This is a natural consequence ofthe fact that, in the present formulation, drug is slowly releasedfrom a predominantly water-insoluble, hydrophobic matrix followingthe degradation of the matrix. The barrier components are degraded,for example, by enzymes, the surfactant action of bile acids andmechanical erosion.
In some embodiments, an immediate release of drug is achievedwithin the stomach in order to provide rapid therapeutic onset.
The pharmaceutical drug composition is administered orally. Theappropriate dosage formulations can be obtained by calculation ofthe pharmacokinetics of the formulation, then adjusting usingroutine techniques to yield the appropriate drug levels based onthe approved dosage forms. Any suitable amount of drug containingmicroparticles or coated microparticles can be included in thefinal formulation. The selection of a suitable amount of drugcontaining microparticles depends on the dosage desired and isreadily determined by those skilled in the art.
In addition to oral administration, some embodiments may also beadministered by other routes, including, but not limited to, rectaland nasal administration. Some embodiments may also be suitable forformulation as oral liquids.
Claim 1 of 30 Claims
1. An orally administrable abuse-deterrent pharmaceuticalcomposition comprising a therapeutically effective amount ofmicroparticles consisting of (a) a lipophilic drug prone to abuseor lipophilic derivative of a drug prone to abuse, and (b) one ormore carrier materials selected from the group consisting of fats,fatty substances, waxes, wax-like substances and mixtures thereof,wherein the drug is dispersed within the one or more carriermaterials, and the release of a portion of incorporated drug isretarded when the physical integrity of the composition iscompromised and the compromised composition is exposed to water.
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