Oral administration form for peptide pharmaceutical substances, in particular insulin

• US 5,614,219 A
• Filed: 09/13/1994
• Issued: 03/25/1997
• Est. Priority Date: 12/05/1991
• Status: Expired due to Term

• Current Assignee: Alfatec-Pharma GmbH
• Original Assignee: Alfatec-Pharma GmbH
• Inventors: Freidenreich, Jurgen, Werry, Jurgen, Wunderlich, Jens-Christian, Schick, Ursula
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Spear, James M.
• Application Number:
  US08/244,691
• Time in Patent Office: 924 Days
• Field of Search: 424/472, 424/469, 424/484, 424/464, 424/465, 424/468, 424/474, 514/774
• US Class Current: 424/472
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 9/1658 Proteins, e.g. albumin, gelatin
• CPC Class Codes: A61K 9/2063 Proteins, e.g. gelatin
• CPC Class Codes: A61K 9/209 containing drug in at least two layers or in the core and in at least one outer layer
• CPC Class Codes: A61K 9/5084 Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs tablets containing such a mixture A61K9/2077
• CPC Class Codes: A61K 9/5169 Proteins, e.g. albumin, gelatin
• CPC Class Codes: G03C 2001/0471 Isoelectric point of gelatine

Abstract

A peroral administration form for peptidic medicaments contains the peptidic medicament, in particular insulin, distributed in a gelatine or gelatine derivate matrix, besides usual pharmaceutical excipients and additives. By selecting an appropriate gelatine, the medicament is released in the small or large intestine, so that it is no longer enzymatically decomposed by peptidases.

Claims

1. An oral administration form for peptide medicaments, containing at least one peptide pharmaceutical substance in a matrix of gelatin, fractionated gelatin or collagen hydrolyzate which dissolves under physiological conditions, in addition to pharmaceutically customary excipient and auxiliaries, the peptide pharmaceutical substance(s) present in colloidal or dissolved form possessing a charge and the molecules of the matrix-forming agent possessing an opposite charge wherein the gelatin has a molecular weight distribution whose maximum is at 10⁴ to 10⁷ D and wherein a layer construction is present.

11. An oral administration form for peptide medicaments as in claim 1 wherein the peptide pharmaceutical substance is insulin.

2. An oral administration form for peptide medicaments, containing at least one peptide pharmaceutical substance in a matrix of gelatin, fractionated gelatin or collagen hydrolyzate which dissolves under physiological conditions, in addition to pharmaceutically customary excipient and auxiliaries, the peptide pharmaceutical substance(s) present in colloidal or dissolved form possessing a charge and the molecules of the matrix-forming agent possessing an opposite charge which is provided with a synthetic or natural coating.

3. An oral administration form for peptide medicaments as in claim 2, which is constructed as a layered tablet.

10. An oral administration form for peptide medicaments as in claim 2 wherein the peptide pharmaceutical substance is insulin.

4. An oral administration form for peptide medicaments, containing at least one peptide pharmaceutical substance in a matrix of gelatin, fractionated gelatin or collagen hydrolyzate which dissolves under physiological conditions, in addition to pharmaceutically customary excipient and auxiliaries, the peptide pharmaceutical substance(s) present in colloidal or dissolved form possessing a charge and the molecules of the matrix-forming agent possessing an opposite charge wherein a time-controlled first form is combined with a second form that dissolves at a faster rate than the first form.

5. An administration form as in claim 4, wherein from the outside the first layer or the coat contains a depot form, while the second layer or the core contains an immediate-effect form.

6. A process for the production of an oral administration form for peptide medicaments, which comprises

a) selecting a gelatin, fractionated gelatin, or collagen hydrolyzate according to its isoelectric point (IEP) such that its IEP is matched with the charge state of the pharmaceutical substance particles such that the gelatin leads to charge neutrality with the undissolved pharmaceutical substance at a specific pH,

b) the gelatin, fractionated gelatin or collagen hydrolyzate is converted into the aqueous sol form,

c) the pH is adjusted as a function of the IEP of the gelatin to such a value that the nanoparticles of the pharmaceutical substance forming are almost or completely stabilized in a neutrally charged manner, and

d) before or after stage c), the pharmaceutical substance is dissolved in the aqueous sol or a solution of the pharmaceutical substances is combined with the aqueous sol.

12. The process as in claim 6 wherein the pharmaceutical substance is insulin.

7. A process for the production of an oral administration form for peptide medicaments, which comprises

a) selecting a gelatin, or fractionated gelatin with a maximum in the molecular weight distribution in the range from 10⁴ -10⁷ D, which is free from foreign ions, wherein the gelatin has a content of microgel of greater than 10% by weight,

b) convening the gelatin or fractionated gelatin into the sol form with water at a temperature above 37°

C. and below the inactivation temperature of the peptide,

c) adjusting the pH of the sol to a value between that of the IEP of the gelatin or fractionated gelatin and that of the peptide,

d) adding the peptide in dissolved or undissolved form to the sol and optionally dissolving in the sol,

e) removing the water,

f) pressing the powder obtained to give the administration form by customary processes and

g) optionally coating the shaped article with a film-forming agent.

9. The process as in claim 7 wherein the stages a) to e are carried out with a second gelatin or a collagen hydrolyzate which contains a maximum in the molecular weight distribution below 10⁵, and stage f) comprises pressing the two powders obtained to give two layer or layered tablets.

8. A process for the production of an oral administration form for peptide medicaments, which comprises preparing a powdered gelatin/pharmaceutical substance mixture with a gelatin, fractionated gelatin, or collagen hydrolyzate, which dissolves in physiological medium under physiological conditions, and compressing the mixture.

13. A process for the production of an oral administration form for insulin medicaments, which comprises

a) selecting a gelatin, or fractionated gelatin with a maximum in the molecular weight distribution in the range from 10⁴ -10⁷ D, which is free from foreign ions,

b) converting the gelatin or fractionated gelatin into the sol form with water at a temperature above 37°

C. and below the inactivation temperature of the insulin,

c) adjusting the pH of the sol to a value between that of the IEP of the gelatin or fractionated gelatin and that of the insulin,

d) adding the insulin in dissolved or undissolved form to the sol and optionally dissolving in the sol,

e) removing the water,

f) pressing the powder obtained to give the administration form by customary processes and

g) optionally coating the shaped article with a film-forming agent.