Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2001-03-14
2004-08-03
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
Reexamination Certificate
active
06770293
ABSTRACT:
the present invention relates to soft capsules, for example for pharmaceutical applications, comprising polymers prepared by polymerization of vinyl esters in the presence of polyethers, and, where appropriate, in the presence of structure-improving auxiliaries and/or other conventional shell constituents, and to the use and production thereof.
Soft capsules are distinguished by the fact that the production of the shell and the filling take place virtually simultaneously in one stop. The shell of such capsules are often also referred to as soft gelatin, which is why the capsules are of ten also referred to as soft gelatin capsules. Since geltain is per se a brittle material of low flexibility, it must be plasticizers are low molecular weight compounds, ordinarily liquids such as, for example, glycerol, propylene glycol, polyethylene glycol 400. Such capsules often additionally contain dyes, opacifying agents and preservatives.
Although gelatin is frequently employed, it has numerous disadvantages. Thus, gelatin is a material of animal origin and thus not kosher. In addition, there is always a slight residual risk of BSE, because gelatin from cattle is preferably used to produce it. Obtaining suitable gelatin is very complicated and requires strict supervision of the process. Despite this, difference between batches are large because of the animal origin, which is subject to a certain variability. Gelatin is very susceptible to microbes because it represents a good nutrient medium for microorganisms. It is therefore necessary to take appropriate measures during the production as well as the use of such packing materials. The use of preservatives is frequently indispensible.
The plasticizers which are absolutely necessary to produce gelatin capsules 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. In addition, the shell of a soft gelatin capsule has a relatively high water content, which likewise has a plasticizing effect. On storage of such capsules with pure humidity there is evaporation of water from the shell, which likewise makes the capsule brittle. The same thing happens when very hygroscopic materials are encapsulated. Particularly hygroscopic or hydrolysis-sensitive substances cannot be encapsulated at all.
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.
Soft gelatin capsules very readily stick together under warm and moist conditions.
The adhesion of film coatings to soft gelatin capsules is extremely poor. For them it is frequently necessary first to apply a special subcoating, which is inconvenient.
Because of these many disadvantages, there has been no lack of attempts to replace gelatin wholly or partly in soft 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 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.
U.S. Pat. No. 5,342,626 describes a combination of gellan, carrageenan and mannan for producing soft capsules or microcapsules. All these components are of natural origin and are subject to the natural variations in quality. Low molecular weight plasticizers are necessary and the products become brittle when the ambient humidity is low. Similar is true of the soft or hard capsules made of carrageenan which are described in the application WO 99/07347.
WO 91/19487 describes a combination of a cationic polymer and an anionic polymer. It is evident merely from the data given that the flexibility changes greatly with the ambient humidity; it decreases greatly when the humidity becomes less. This is understandable because the charges on the polymers greatly attract water. The line between polymer mixtures which are too tacky and too brittle is stated to be very narrow. The charges on the polymers may lead to interactions with the filling material and the drugs, especially since most drugs are likewise charged.
WO 99/40156 describes combinations of polyethylene glycols of various molecular weights which are suitable for producing films or soft capsules. However, polyethylene glycols with a high molecular weight dissolve only slowly in water and are brittle. Although combination with polyethylene glycols with a very low molecular weight makes them somewhat more flexible, they also become more tacky. In addition, they may in turn migrate into the filling because of their low molecular weight.
The application WO 98/27151 describes a mixture of cellulose ethers and polysaccharides plus sequestering agents, where the cellulose ether represents the main constituent (90 to 99.98%) for producing hard and soft capsules. Because of the brittleness of the cellulose ethers, this preparation is suitable without plasticizers at the most for hard gelatin capsules and, if plasticizers are added, the abovementioned disadvantages reappear. The rate of dissolution of such capsules is likewise unsatisfactory.
DE-A2 2 363 853 describes the use of partially hydrolyzed copolymers of vinyl acetate on polyethylene glycol for producing hard capsules for medicines. There are no references in this publication to the use of the copolymers for producing soft capsules.
However, the requirements to be met by hard capsules are quite different from those for soft capsules. Hard capsules require great strength, while flexibility is a priority with soft capsules. The production processes also differ entirely. In the case of hard capsules, firstly only the shell is produced in 2 separate parts, a cap and a body, by a dip process, whereas in the case of soft capsules the shell and the filling are produced virtually simultaneously.
In the case of hard capsules, after production of cap and body these are loosely fitted together so that the pharmaceutical manufacturer is able to separate the two parts again mechanically, introduce his powder and close the capsule. Detailed examination of this processing makes it clear that the two capsule parts must be very mechanically stable, especially since the filling machines operate very rapidly and changes in shape would bring the entire process to a stop.
In the case of soft capsules, the shell must firstly be absolutely leakproof so that the filling, which is usually liquid, cannot escape, and secondly very flexible because the filling would otherwise escape through cracks or microfissures. Particularly high flexiblity is necessary for production because the polymer film is sucked into drilled cavities and is thus greatly deformed and stretched. The production of soft capsules is a technologically very demanding process, which is why the polymer properties and the machines must be harmonized and adjusted accurately.
The entirely different processes for producing hard and soft gelatin ca
Angel Maximilian
Gotsche Michael
Kolter Karl
Sanner Axel
BASF - Aktiengesellschaft
Joynes Robert M.
Keil & Weinkauf
Page Thurman K.
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