Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2001-03-20
2004-08-31
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
Reexamination Certificate
active
06783770
ABSTRACT:
The present invention relates to hard capsules, for example for pharmaceutical applications, comprising polymers prepared by polymerization of vinyl esters and, where appropriate, another free-radically copolymerizable monomer in the presence of a polyether-containing compound, and subsequent at least partial hydrolysis, comprising structure-improving auxiliaries and other conventional shell constituents, their use and production.
Hard capsules are distinguished by being produced as empty capsules which are in two pieces which fit together, and being filled and closed only after production. The hard capsules are in most cases produced from aqueous solution in the so-called dip process (S. Stegmann, PZ Prisma, 5, 42-56, 1998). A review of the prior art in injection molding for producing pharmaceutical hard capsules from starch or gelatin is given by L. Eith et al. in Drug Dev. Ind. Pharm., 12, 2113-2126 (1986). On detailed examination of this processing, it is clear that the two parts of the capsule must be very mechanically stable, especially since the filling machines are very fast-running and dimensional changes would have very adverse effects on the filling process.
Since the two molded parts are tightly fitted together after filling, it is necessary that the capsule material has adequate dimensional stability.
In addition, hard capsules for medical applications are frequently packed in so-called blister packs to increase the storage stability. When the hard capsules are pushed out of these packs, mechanical stress occurs and must not lead to deformation of the hard capsules. It is therefore necessary for hard capsules to have adequate mechanical stability.
To date, hard capsules for pharmaceutical dosage forms have been mainly produced from gelatin. However, gelatin has some crucial disadvantages. Thus, gelatin is a material of animal origin and is thus not kosher. In addition, there is always a slight residual risk of BSE because gelatin from cattle is preferably used to produce them. Obtaining a suitable gelatin is very complicated and requires strict monitoring of the process. Nevertheless, differences between batches are large because of the animal origin, which is subject to a certain variability. Gelatin is very microbially susceptible because it represents a good nutrient medium for microorganisms. Appropriate measures must therefore be taken during production and use of such packaging materials. The use of preservatives is frequently indispensable.
Since gelatin is per se a brittle material of low flexibility, it must be plasticized appropriately, i.e. plasticizers must be added in the form of low molecular weight compounds. These plasticizers which are necessary frequently migrate from the shell into the filling and cause changes there. The shell loses plasticizers and becomes brittle and mechanically unstable during the course of storage.
The rate of dissolution of gelatin is relatively slow. A higher rate of dissolution in gastric or intestinal fluid would be desirable for rapid release of active ingredients.
Numerous substances lead to interactions with gelatin, such as, for example, aldehydes, polyphenols, reducing sugars, multiply charged cations, electrolytes, cationic or anionic polymers etc., with crosslinking frequently occurring and the capsule then disintegrating or dissolving only very slowly or not at all. Such changes are catastrophic for a drug product because efficacy is lost. Many drugs also lead to interactions with gelatin. In some cases during storage there is formation of drug degradation products with, for example, an aldehyde structure, which lead to crosslinking of the gelatin. Since gelatin has both acidic and basic groups, it is clear that reactions easily occur with other charged molecules.
Gelatin can be cleaved by enzymes. Contamination by enzymes or bacteria which release enzymes may drastically alter the properties of gelatin.
Because of these many disadvantages, there has been no lack of attempts to replace gelatin wholly or partly in hard capsules.
Attempts have therefore been made to find synthetic polymers which can be employed to produce hard capsules.
For example, polyvinyl alcohol has been described for this purpose. However, polyvinyl alcohol has a slow rate of dissolution, likewise requires additional plasticizers, which in turn may migrate and which, as already described above, may alter the properties of the filling, and it may moreover become extremely brittle as a consequence of internal crystallization.
In particular, the flexibility decreases drastically during the course of storage if the ambient humidity is low.
JP Sho-45-1277 used, for example, polyvinyl alcohol as base material for hard capsules. DE-A-1 965 584 likewise describes the use of polyvinyl alcohol and other polymers for medicinal hard capsules.
These polymers have not proved to be an adequate substitute for conventional gelatin in the technology and practice of capsule production and use thereof.
DE-A 23 63 853 describes self-supporting packings or capsules for medicines which are produced using graft copolymers of polyvinyl alcohol on polyethylene glycol. The graft copolymers preferred for this application are produced by grafting vinyl acetate onto polyethylene glycol having a molecular weight of from 20,000 to 25,000 and subsequent methanolysis of the vinyl acetate units. Such polymers are very soft and easily deformable.
Graft copolymers of polyvinyl alcohol on polyalkylene glycols have already been described in other patents.
DE 1 077 430 describes a process for producing graft copolymers of vinyl esters on polyalkylene glycols.
DE 1 094 457 and DE 1 081 229 describe processes for producing graft copolymers of polyvinyl alcohol on polyalkylene glycols by hydrolyzing the vinyl esters and the use thereof as protective colloids, water-soluble packaging films, as sizing and finishing agents for textiles and in cosmetics.
The use of the described graft copolymers for hard capsules has not been disclosed.
The polymers described in the prior art to date have inadequate properties for the production of hard capsules because of their elasticity and flexibility.
It is an object of the present invention to find synthetic polymers with greater dimensional stability for producing hard capsules for pharmaceutical dosage forms which are superior to gelatin and many known substitute materials.
We have found that this object is achieved by hard capsules comprising
(A) polymers obtainable by free-radical polymerization of
a) at least one vinyl ester in the presence of
b) polyether-containing compounds and
c) where appropriate one or more other copolymerizable monomers and subsequent at least partial hydrolysis of the ester functions in the original monomers a),
with the proviso that in the absence of another copolymerizable monomer c) the polyether-containing compound b) must have a number average molecular weight ≦10,000,
(B) where appropriate structure-improving auxiliaries and
(C) other conventional shell constituents.
It has moreover been found, surprisingly, that addition of another comonomer c) in the polymerization in particular leads to harder polymers which are suitable for producing hard capsules with improved dimensional stability.
During production of the polymers used according to the invention there may be during the polymerization a grafting onto the polyether-containing compounds (b), which may lead to the advantageous properties of the polymers. However, mechanisms other than grafting are also conceivable.
Depending on the degree of grafting, the polymers used according to the invention comprise both pure graft copolymers and mixtures of the abovementioned graft copolymers with ungrafted polyether-containing compounds and homo- or copolymers of monomers a) and c).
Polyether-containing compounds (b) which can be used are both polyalkylene oxides based on ethylene oxide, propylene oxide, butylene oxide and other alkylene oxides, and polyglycerol. Depending on the nature of the monomer building blocks, the polymers contain the following structural u
Angel Maximilian
Gotsche Michael
Kolter Karl
Sanner Axel
BASF - Aktiengesellschaft
Joynes Robert M.
Keil & Weinkauf
Page Thurman K.
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