Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1994-04-05
2002-10-22
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S003100, C514S773000, C514S774000, C424S472000, C424S464000, C424S465000, C424S468000, C424S469000, C424S474000, C424S484000
Reexamination Certificate
active
06468959
ABSTRACT:
FIELD OF THE INVENTION
The invention concerns a peroral application form for peptide pharmaceuticals, wherein at least one peptide pharmaceutical is distributed in a matrix of gelatin or a gelatin derivative together with pharmaceutically conventional carriers and inactive ingredients. The invention further concerns a process for the preparation of such peroral dosage forms.
BACKGROUND OF THE INVENTION
In highly industrial countries, it may be assumed that from about 2 to about 3% of the population exhibit the symptoms of diabetes. For the effective handling of this disease with its most important symptoms such as hypoglycemia, hyperuresis, glucouria, as well as hypolipidemia, despite enormous and varied pharmaceutical developments, the exogenous administration of insulin is still the mainstay of treatment. Even the orally administrable antidiabetics of the sulfonyl urea type which are only then indicated when the patient's production of insulin is still partially maintained, yield only a limited field of use.
The most substantial administration of insulin is by injection (parenteval application). Other modes of application, for example, nasal, pulmonal, rectal, and especially peroral, are presently under investigation.
At the present time, it is not apparent that an appropriate product has been able to achieve an adequate level of market acceptability. Rather one can say that these alternate modes are in the stage of orientation research. It is well known that injections carry disadvantages. Thus, at the point of application for example, lipodystrophy or other foreign body reactions may occur, Problems with the handling of syringes are particularly to be expected with very young and old patients. A regularly available injection with patient groups must often be undertaken by a trusted person. It is clear that this requirement does not exactly assist in patient compliance.
The optimal, simplest and surest mode of use of pharmaceuticals in contrast, is the peroral application. For example with tablets, capsules, and potable solutions. In the case of peptide pharmaceuticals for example insulin, substantial difficulties arise since these are already inactivated through enzymatic degradation to a substantial extent when released in the gastrointestinal tract (GIT; stomach or small intestine) before absorption. The enzymatic degradation in the gastric or small intestinal fluid, or on the mucosa threatens to reduce the bioavailability of peptide materials in particular, insulin to a minimum. Furthermore, the absorption mechanism for peptide pharmaceuticals by passive transport is substantially unavailable. This is due, on the one hand, to the molecular size, which for passive transport has a limit of about 500 daltons. On the other hand, substance specific properties such as hydrophilicity (lower distribution co-efficient), self association to larger entities, or binding to the components of the gastrointestinal tract interfere with absorption. Furthermore, absorption becomes additionally more difficult when the dissociation of functionally active groups results in a negative charge which leads to electrostatic repulsion at the glycocalise whose negatively charged glycoprotein layer covers the lipid double layer. Absorption of peptide pharmaceuticals is nevertheless, of extraordinary importance if one wishes to successfully avoid parenteral administration.
It has already been suggested to administer insulin encapsulated in liposomes. In these researches however, it appeared nevertheless not to have been possible to determine the absorbed insulin amounts quantitatively. Thus, these researches can only give a rough orientation values. The use of liposomes furthermore, carries with it substantial difficulties both in the production and in the storage of the corresponding pharmaceutical forms.
Recently there have been reports about practical arrangements to facilitate the peroral application of insulin. Particularly of interest are pharmaceutical embodiments which are stomach and small intestine resistant and release the insulin only after reaching the peptidase poor colon.
It has similarly been suggested that insulin should be combined with an absorption accelerator in a soft gelatin capsule (EP application 0225 189) wherein the capsule is provided with a coating which first dissolves in the colon and that the insulin is then released together with the aforementioned absorption accelerator. The addition of a absorption accelerator (for example, certain tensides such as salacyl acid derivatives) in the gastrointestinal tract, nevertheless appears to have limited effectiveness since in view of the substantial dilution occurring there. For this reason a very substantial administered amounts which can reach 50% of the capsule content, can already call forth deleterious side effects. Furthermore, the toxic side effects of tensides particularly on the mucous membrane are well known. Thus substantial questions may be raised with respect to the desirability of employing salicylic acid derivatives as pharmaceutically inactive ingredients.
U.S. Pat. No. 4,849,405 suggests embedding insulin in a fluid, aqueous two phase system in a coaszervate system. The behavior of coaszervates are known to create problems in their production. It is not possible to provide an exact control of the process parameters. The reproduceability of the process must therefore be brought into question. In these coaszervates, the embedded insulin should provide a rapidly releasable dosage form wherein the preparation is provided in liquid (emulsion) form. The shelf stability of this system may be considered to be subject to substantial problems. By heat treatment (hardening) or cross-linking with aldehydes (for example glutaraldehyde), together with the subsequent removal of the microcapsules through filtration and drying, the coaszervate may be converted into a shelf stable, but nevertheless more slowly released pharmaceutically active form. In these procedures however, an activity lost of the insulin through chemical change cannot be excluded. It is known that insulin is not only sensitive with respect to heat, but also that it can hardly be expected to remain inert with respect to aldehydes. Furthermore, generally speaking in the process disclosed in U.S. Pat. No. 4,849,405 a substantial insulin loss during the encapsulation process must be reckoned with, which clearly reflects negatively upon the production costs. There is no report on the yield of encapsulated insulin.
The task of the present invention therefore is to provide a dosasge form suitable for the peroral administration of peptide pharmaceuticals in particular, insulin which avoids the problems described in the state of the art and thus, permit secure and effective treatment.
SUMMARY OF THE INVENTION
The problem of the present invention is solved thereby that a pharmaceutically active material namely a peptide pharmaceutical material, in particular insulin is dissolved in a gelatin matrix together with conventional pharmaceutical carriers and inactive ingredients.. Furthermore, this task is solved thereby that the peptide pharmaceutically active material in particular insulin, is associated as a charged molecule by absorptive charge compensation (pseudo coaszervate) with an oppositely charged gelatin. Finally, the task is also solved by absorptive charge compensation (pseudo coaszervate) on a contrary charged gelatin associated system, of a peptide pharmaceutical in particular, insulin for the formation of the dosage form, which leads to a safe and effective treatment of the symptoms of diabetes.
In particular, the present invention makes available a peroral dosage form for peptide pharmaceuticals comprising at least one peptide pharmaceutical in a matrix which, besides the usual pharmaceutical carriers and inactive ingredients, contain at least one hydrophilic molecule selected from the group consisting of gelatin, fractionated gelatin, collagen hydrolysates, gelatin derivatives, as well as mixtures thereof.
Furthermore, the present invention among ot
Freidenreich Jurgen
Schick Ursula
Werry Jurgen
Wunderlich Jens-Christian
ALFATEC-Pharm GmbH
Low Christopher S. F.
Lukton David
Selitto Behr & Kim
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