Rapidly Disintegrable solid preparation

Tag : vacuum forming molding


The "low-substituted hydroxypropylcellulose having 5% byweight or more to less than 7% by weight of hydroxypropoxyl group(hereinafter, optionally referred to L-HPC)" used in thepresent invention can be produced in accordance with well-knownmethods, for example, methods described in JP-B-57-53100 or itsanalogous methods thereof.

At first, alkaline cellulose containing free alkaline and propyleneoxide are reacted to obtain the crude low-substitutedhydroxypropylcellulose containing free alkaline.

Concretely, for example, raw material pulp such as wood pulp andcotton leader is immersed in 10 to 50% concentration of aqueoussolution of sodium hydroxide, and pressed to obtain the alkalinecellulose of which NaOH/cellulose ratio is 0.1 to 1.2 (ratio byweight). Next, the crude low-substituted hydroxypropylcellulosecontaining free alkaline is obtained by reacting the resultingalkaline cellulose and propylene oxide with stirring at 20 to90.degree. C. for 2 to 8 hours. Propylene oxide is used in anamount so that the content of hydroxypropoxyl group in the desiredlow-substituted hydroxypropylcellulose can be 5% or more by weightto less than 7% by weight.

The crude low-substituted hydroxypropylcellulose containing freealkaline is dispersed in water or hot water containing 5 to 80% ofacid which is need to neutralize all the amount of alkaline, and apart of the crude low-substituted hydroxypropylcellulose containingfree alkaline is dissolved therein. Further, acid is added toneutralize the remaining alkaline.

After the neutralization, processes such as drainage, drying andgrinding are performed in accordance with the conventional methodto obtain the desired low-substituted hydroxypropylcellulose.

The particle diameter of L-HPC used in the present invention is,for example, 5 to 60 .mu.m as average particle diameter.Preferably, it is 10 to 40 .mu.m as average particle diameter.

In the above ranges, in case that L-HPC having relatively largeparticle diameter (for example, L-HPC having 26 to 40 .mu.m ofaverage particle diameter) is used, a pharmaceutical preparationbeing superior in disintegrability can be produced. On the otherhand, in case that L-HPC having relatively small particle diameter(for example, L-HPC having 10 to 25 .mu.m of average particlediameter) is used, the pharmaceutical preparation being superior instrength of the preparation can be produced.

Accordingly, the particle diameter of L-HPC can be suitablyselected according to the character of the desired pharmaceuticalpreparation.

In order to obtain sufficient strength of the preparation andsufficiently fast disintegrability, the L-HPC in the presentinvention is used in an amount of 3 to 50 parts by weight,preferably 5 to 40 parts by weight, per 100 parts by weight of thesolid preparation in case of the solid preparation not comprisingfine granules. On the other hand, the L-HPC in the presentinvention is used in an amount of 3 to 50 parts by weight,preferably 5 to 40 parts by weight, per 100 parts by weight of therest of the solid preparation other than the fine granules in caseof the solid preparation comprising fine granules.

As mentioned above, by using L-HPC, it becomes possible to improvefast disintegrability, particularly the orally fastdisintegrability, of the solid preparation containing thepharmacologically active ingredient and the sugar.

As the dosage form of the rapidly disintegrable solid preparationof the present invention, for example, tablet, granule, finegranule and the like, preferably tablet is exemplified. Amongrapidly disintegrable tablets such as an orally disintegrabletablet and a tablet disintegrable in water, the orallydisintegrable tablet is preferable.

Unless fast disintegrability (particularly, fast disintegrabilityin the oral cavity) or strength of the preparation is interferedwith, the rapidly disintegrable solid preparation of the presentinvention may further contain a variety of additives which arecommonly used in the manufacture of preparations in general dosageforms. Amount of such additives to be used is one commonly used inthe manufacture of preparations in general dosage forms. As suchadditives, for example, binders, acids, foaming agents, artificialsweeteners, flavorants, lubricants, colorants, stabilizers,excipients, disintegrators and the like are exemplified.

As the above binders, for example, hydroxypropylcellulose,hydroxypropylmethylcellulose, crystalline cellulose, pregelatinizedstarch, polyvinylpyrrolidone, gum arabic powder, gelatin, pullulanand the like are exemplified. These two or more binders can be usedin an admixture in a given ratio. The use of crystalline celluloseas the binder provides the solid preparation which exhibits moreexcellent strength of the preparation while retaining excellentfast disintegrability in the oral cavity. As the crystallinecellulose, microcrystalline cellulose is also included. The"crystalline cellulose" includes a refined one havingpartially .alpha.-cellulose depolymerization. As crystallinecellulose, for example, CEOLUS KG 801, Avicel PH 101, Avicel PH102, Avicel PH 301, Avicel PH 302, Avicel RC-A591 NF (crystallinecellulose.carmellose sodium), Avicel RC-591 (crystallinecellulose.carmellose sodium) and the like are concretelyexemplified. Among them, CEOLUS KG 801 referred to as highlymoldable crystalline cellulose is preferably used. Such crystallinecelluloses are optionally used in an admixture thereof withsuitable ratio. Such crystalline celluloses can be commerciallyavailable (manufactured by Asahi Chemical Industry Co., Ltd.(Japan)). The crystalline cellulose is used in an amount of, forexample, 1 to 50 parts by weight, preferably 2 to 40 parts byweight, more preferably 2 to 20 parts by weight, per 100 parts byweight of the solid preparation in case of the solid preparationnot comprising fine granules. Likewise, the crystalline celluloseis used in an amount of, for example, 1 to 50 parts by weight,preferably 2 to 40 parts by weight, more preferably 2 to 20 partsby weight, per 100 parts by weight of the solid preparation apartfrom fine granules in case of the solid preparation comprising finegranules.

As the acids, for example, citric acid, tartaric acid, malic acidand the like are exemplified.

As the foaming agents, for example, sodium bicarbonate and the likeare exemplified.

As the artificial sweeteners, for example, saccharin sodium,dipotassium glycyrrhizinate, aspartame, stevia, thaumatin and thelike are exemplified.

As the flavorants, for example, lemon, lemon lime, orange, mentol,strawberry and the like are exemplified.

As the lubricants, for example, magnesium stearate, sucrose fattyacid ester, polyethylene glycol, talc, stearic acid and the likeare exemplified. Use of polyethylene glycol as the lubricantprovides the stable solid preparation of which the decompositionover time of the pharmacologically active ingredient is controlled.At that time, polyethylene glycol is used in an amount of, forexample, 0.01 to 10 parts by weight, preferably 0.1 to 5 parts byweight, per 100 parts by weight of the solid preparation in case ofthe solid preparation not comprising fine granules. Likewise,polyethylene glycol is used in an amount of, for example, 0.01 to10 parts by weight, preferably 0.1 to 5 parts by weight, per 100parts by weight of the solid preparation apart from fine granulesin case of the solid preparation comprising fine granules.

As the colorants, for example, various food colorants such as FoodYellow No. 5, Food Red No.2, Food Blue No. 2 and the like; foodlakes, red iron oxide and the like are exemplified.

As the stabilizers, for example, a basic substance in the case ofthe basic pharmacologically active ingredient and an acidicsubstance in the case of the acidic pharmacologically activeingredient are exemplified.

As the excipients, for example, lactose, sucrose, D-mannitol,starch, corn starch, crystalline cellulose, light silicicanhydride, titanium oxide and the like are exemplified.

Two or more of these disintegrants can be as a mixture in a givenratio. For example, (i) crospovidone solely, or (ii) crospovidoneand another disintegrant(s) is preferably used.

Such disintegrator is used in an amount of, for example, 0.1 to 20parts by weight, preferably 1 to 10 parts by weight, morepreferably 3 to 7 parts by weight, per 100 parts by weight of thesolid preparation in case of the solid preparation not comprisingfine granules. Likewise, such disintegrator is used in an amountof, for example, 0.1 to 20 parts by weight, preferably 1 to 10parts by weight, more preferably 3 to 7 parts by weight, per 100parts by weight of the rest of the solid preparation other than thefine granules in case of the solid preparation comprising finegranules.

In case that the pharmacologically active ingredient is anacid-labile one such as lansoprazole, omeprazole, rapeprazole,pantoprazole and the like, a basic inorganic salt is preferablyincorporated to stabilize the pharmacologically active ingredientin the solid preparation.

The "basic inorganic salt" includes, for example, a basicinorganic salt of sodium, potassium, magnesium and/or calcium,preferably a basic inorganic salt of magnesium and/or calcium.Among others, preferred is a basic inorganic salt of magnesium.

The basic inorganic salt of sodium includes, for example, sodiumcarbonate, sodium hydrogencarbonate, sodium phosphate, sodiumhydrogenphosphate and the like.

The basic inorganic salt of potassium includes, for example,potassium carbonate, potassium hydrogencarbonate, potassiumphosphate, potassium hydrogenphosphate, potassium sodium carbonateand the like.

The basic inorganic salt of magnesium includes, for example, heavymagnesium carbonate, magnesium carbonate, magnesium oxide,magnesium hydroxide, magnesium metasilicate aluminate, magnesiumsilicate aluminate, magnesium silicate, magnesium aluminate,synthetic hydrotalcite[Mg.sub.6Al.sub.2(OH).sub.16.CO.sub.3.4H.sub.2O], aluminummagnesium hydroxide [2.5MgO.Al.sub.2O.sub.3.xH.sub.2O] and thelike. Among others, preferred is heavy magnesium carbonate,magnesium carbonate, magnesium oxide, magnesium hydroxide and thelike.

The basic inorganic salt of calcium includes, for example,precipitated calcium carbonate, calcium hydroxide, and the like.

The preferable examples of the "basic inorganic salt" aremagnesium basic inorganic salt, and more preferable examplesinclude heavy magnesium carbonate, magnesium carbonate, magnesiumoxide, magnesium hydroxide, and the like.