Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-09-28
2001-03-20
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S010100, C424S452000, C424S455000
Reexamination Certificate
active
06204243
ABSTRACT:
The invention relates to a pharmaceutical preparation for the enteral treatment of Crohn's disease and ulcerative colitis, which contains an immunosuppressive active agent, which is administered in the form of a special galenic formulation for targeted local activity in the intestinal area, its use and a process for the production thereof.
The therapies known today for the treatment of Crohn's disease and ulcerative colitis are not very effective. At the end of drug treatment, the patient usually faces surgical intervention. There are numerous preparations for extending and improving the therapeutical possibilities, but until now no preparation has been able to meet the medicinal requirements to a maximum degree.
One possibility of local, enteral therapy of inflammatory intestinal affections was opened up with the development and usage of special mesalazine-containing (5-aminosalicylic acid) preparations, which release the active agent in the distal part of the small intestine and in the large intestine. The preparations concerned are solid forms of administration, which contain the active agent in crystalline form despite its poor solubility.
A new possibility is represented by the use of immunosuppressive active agents which are more effective than the salicylic acid derivatives, but when applied systemically in therapeutically effective dosages have considerable side effects.
The present invention is based on the problem of making available a pharmaceutical preparation for the targeted treatment of Crohn's disease and ulcerative colitis, which contains an immunosuppressive active agent. The activity of the preparation should be targeted at the small and large intestines, and the preparation should ensure local, enteral application of the immunosuppressive active agent at the site of occurrence of the inflammatory disorder.
Surprisingly, an improvement in the rate of effect over the side effects of the immunosuppressive active agent, i.e. a broadening of the therapeutical range, is achieved through the local application of the active agents in the form of a new pharmaceutical preparation, which transports the active agent to the site of occurrence of the inflammatory disorder and allows optimum activity there.
The immunosuppressive active agents from the group of macrolides claimed here are poorly soluble in aqueous media, e.g. in the lumen of the gastrointestinal tract. The dissolution conditions are extremely unfavourable for poorly soluble active agents owing to the small amount of fluid available, especially in the area being envisaged for activity of the preparation, the distal small intestine and the large intestine. As a consequence thereof, the active agent should advantageously be transported to the site of the disorder in an already dissolved form. To this end, ideally, a solution of the active agent is filled into starch capsules, or hard or soft gelatin capsules. The unmodified gelatin capsule or starch capsule does not survive transit through the stomach and the upper small intestine area.
Undesired dissolution of the capsule shell in the area of the stomach or upper small intestine is prevented by coating the external capsule wall with a polymer film. The choice and usage of appropriate polymers, including additional materials such as softeners and pore-forming agents, control the site of dissolution of the capsule and the release of solution containing the active agent.
The object of the invention is a pharmaceutical preparation which contains an immunosuppressive active agent in dissolved form in a starch capsule, or hard or soft gelatin capsule which is coated with one or several polymer films.
A further object of the invention is a process for the production of the preparation according to the invention, which is characterised in that the active agent is dissolved in a solvent which is suitable for encapsulation into starch or gelatin capsules, or in a mixture of several solvents and optionally solubilizers and/or other excipients, the solution is then filled in a manner known per se into starch capsules, or hard or soft gelatin capsules in a measured dose, the capsules are sealed and the capsules are coated with a solution or dispersion of a polymer or polymer mixture and dried, whereby the coating procedure may be repeated once or several times.
The preparation according to the invention is suitable for the local, enteral treatment of Crohn's disease and ulcerative colitis. It contains an immunosuppressive active agent which is poorly soluble in water. The preparation according to the invention contains as active agent rapamycin, tacrolimus, cyclosporin A or combinations of these active agents. The solvents that are appropriate for dissolving the active agent are those that are pharmaceutically acceptable and in which the active agent dissolves.
Examples of these are ethanol, 1,2-propylene glycol, glycerol, polyethylene glycol 300/400, benzyl alcohol, medium-chained triglycerides and vegetable oils.
If required, the usual medicament excipients may be added to the solution of active agent and solvent, for example surface-active agents and agents which affect viscosity. Examples of such excipients are mono-/di-fatty acid glycerides, sorbitan fatty acid esters, polysorbates, Mirj® 52, lecithin, sodium lauryl sulphate, sodium dioctylsulphosuccinate, Cremophor® RH40EL, aerosil and water-soluble cellulose derivatives.
Mixtures of solvents and the above-mentioned excipients may also be used. The concentration of active agent in the solvent or mixture is adjusted such that it lies between 0.2 and 20% (weight/weight), preferably between 1 and 15% (weight/weight), particularly preferred between 2 and 10% (weight/weight). The solution of the active agent is filled into a conventional starch capsule, or soft or hard gelatin capsule in an amount of 0.05 ml to 2 ml, preferably in an amount of 0.1 to 1.4 ml. The gelatin capsules or starch capsules employed may be those that are normally used in the pharmaceutical field and that are available commercially. If desired, the capsule may be additionally provided with a sealing strip, in order to prevent the solution of active agent from escaping. Production of the soft gelatin capsules is effected for example analogously to the known Scherer processes. The starch capsules are available under the commercial name Capill®.
To enable local enteral application of the immunosuppressive active agents deoxy-spergualin, rapamycin, tacrolimus, and cyclosporin A to take place, after swallowing the capsule, there must be passage of the intact capsule through the stomach and the upper small intestine region. To this end, the soft or hard gelatin capsule is coated with one or several polymer films, whereby the targeted capsule dissolution and release of active agent is achieved through the film composition. Two principles or a combination of these principles may be offered for this purpose:
1. Premature dissolution of the capsule is prevented by coating the capsule with a polymer film containing acid groups, whereby the type of acid and the number of acid groups control dissolution of the film in dependence of the pH value of the surroundings.
2. Dissolution of the capsule is controlled by diffusion mechanisms, whereby the polymer film is insoluble in water and the diffusion operations are influenced by additional substances such as water-soluble pore forming agents and softeners.
Within the sense of this invention, especially suitable polymers for principle 1 are:
Cellulose-acetate trimellitate, -acetate succinate, -acetate phthalate, hydroxypropyl methylcellulose phthalate, -acetate succinate, carboxymethylethyl cellulose (Trade name e.g. Duodcell®), polyvinyl acetate phthalate (commercial products, e.g. Coateric®, Opadry Enteric®), copolymerisates of vinyl acetate and crotonic acid (commercial product, e.g. Coating CE 5142®), polymethacrylates, e.g. copolymerisates of methacrylic acid and methyl-methacrylate, copolymerisates of methacrylic acid and ethyl acrylate (commercial products are e.g. Eudragit® L/L30D). Mix
Krass Frederick
Novatis AG
Thallemer John D.
LandOfFree
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