Novel processes for the manufacture of pharmaceutical compositions

Abstract

This invention provides a novel process for producing compositions useful in the field of drug delivery. [Solution] A process is provided for preparing a composition in the form of multiple particles having an average diameter of 10 nm to about 700 μm based on weight, number, and / or volume. These particles comprise (a) a solid core, preferably containing a biologically active agent, and (b) two or more sequentially coated individual layers, each containing at least one separately coated coating material, the two or more layers together surround and / or encapsulate the core. If the core contains a biologically active agent, the composition may provide a delayed or sustained release of the agent without a burst effect.

Claims

1. A method for preparing a composition in the form of multiple particles having an average diameter based on weight, number, and / or volume of 10 nm to 700 μm, wherein the particles are (a) A spray-dried solid core containing a biologically active agent, (b) Two or more sequentially coated individual layers, each comprising at least one distinct coating material, the two or more layers together surround, enclose, and / or encapsulate the core, The above method involves the following steps: (1) A step of applying at least one initial layer of coating material to the solid core by vapor deposition technology, (2) Remove the coated particles from the gas phase deposition reactor, and subject the coated particles to stirring and deagglomerate the particle aggregates formed in step (1) by mechanical sieving technique. (3) The steps of reintroducing the deaggregated coated particles from step (2) into the gas phase deposition reactor and applying at least one additional layer of coating material to the reintroduced particles, (4) The step of repeating steps (2) and (3) one or more times to increase the total thickness of the at least one coating material surrounding the solid core, Here, the mechanical sieving technique includes means of passing the coated particles through a sieve located outside the reactor by a mechanical and / or automated method. method.

2. The method according to claim 1, wherein the core comprises a pharmaceutically acceptable excipient.

3. The method according to claim 2, wherein the pharmaceutically acceptable excipient is a sugar or a sugar alcohol and / or a pH modifier.

4. The method according to claim 1, wherein the core comprises an intrinsically biologically active agent.

5. The aforementioned biologically active agents include analgesics, anesthetics, anti-ADHD agents, appetite suppressants, antitoxic agents, antibacterial agents, antimicrobial agents, antifungal agents, antiviral agents, antiparasitic agents, antiprotozoal agents, anthelmintics, ectoparasitic agents, vaccines, anticancer agents, antimetabolites, alkylating agents, antitumor agents, topoisomerases, immunomodulators, immunostimulants, immunosuppressants, anabolic steroid solutions, anticoagulants, antiplatelet agents, anticonvulsants, antidementia agents, antidepressants, antitoxin agents, antihyperlipidemic agents, antigout agents, antimalarial agents, antimigraine agents, anti-inflammatory agents, antiparkinsonian agents, antipruritic agents, antipsoriasis agents, antiemetics, antiobesity agents, anthelmintics, and antiasthma agents. Breathing agents, antibiotics, antidiabetic agents, antiepileptic drugs, antifibrinolytic agents, antihemorrhagic agents, antihistamines, antitussives, antihypertensives, antimuscarinic agents, antimycobacterial agents, antioxidants, antipsychotics, antipyretics, antirheumatic agents, antiarrhythmics, anti-anxiety agents, aphrodisiacs, cardiac glycosides, cardiac stimulants, enterogens, enteractogens, anesthetics, orexogenics, antithyroid agents, anxiolytics, hypnotics, nerve relaxants, astringents, bacteriostatic agents, beta-blockers, calcium channel blockers, ACE inhibitors, angiotensin II receptor antagonists, renin inhibitors, beta-adrenergic receptor blockers, blood Liquid products, blood substitutes, bronchodilators, cardiac antiarrhythmic drugs, chemotherapy drugs, coagulants, corticosteroids, cough suppressants, diuretics, deliant agents, expectorants, fertilizers, sex hormones, mood stabilizers, mucolytics, neuroprotective agents, nootropics, neurotoxins, dopamine agonists, antiparkinson's disease drugs, free radical scavengers, growth factors, fibrates, bile acid blockades, desarcolytics, glucocorticoids, mineralocorticoids, hemostatic agents, hallucinogens, hypothalamic-pituitary hormones, immunosuppressants, laxatives, antidiarrheal agents, lipid regulators, muscle relaxants, parasympathomimetic agents, parathyroid calcitonin, Celenic, S Tachin, stimulants, stimulants, decongestants, dietary minerals, biphosphonates, cough suppressants, ophthalmic drugs, ontology drugs, H1 antagonists, H2 antagonists, proton pump inhibitors, prostaglandins, radiopharmaceuticals, hormones, sedatives, anti-allergic drugs, appetite stimulants, steroids, sympathomimetic drugs, thrombolytics, thyroid drugs, vasodilators, xanthines, erectile dysfunction drugs, gastrointestinal drugs, histamine receptor antagonists, keratolytics, antianginal agents, nonsteroidal anti-inflammatory drugs, COX-2 inhibitors, leukotriene inhibitors, macrolides, NSAIDs, nutritional supplements, opioid analgesics,The method according to any one of claims 2 to 4, selected from opioid antagonists, potassium channel activators, protease inhibitors, anti-osteoporosis drugs, cognitive enhancers, anti-urinary incontinence drugs, nutritional oils, anti-benign prostatic hyperplasia drugs, essential fatty acids, non-essential fatty acids, cytokines, peptide mimetic drugs, peptides, proteins, radiopharmaceuticals, anti-senile drugs, toxoids, serum, antibodies, nucleosides, nucleotides, vitamins, parts of genetic material, nucleic acids, or mixtures thereof.

6. The method according to any one of claims 1 to 5, wherein the average diameter of the cores, based on weight, number, or volume, is in the range of 1 μm to 50 μm.

7. The method according to any one of claims 1 to 6, wherein 3 to 10 individual layers of the coating material are sequentially applied to the core.

8. The method according to any one of claims 1 to 7, wherein the total thickness of the individual layers of the coating material is 0.5 nm to 2 μm.

9. The method according to any one of claims 1 to 8, wherein the maximum thickness of each individual layer of the coating material is one-hundredth of the average diameter of the core based on its weight, number, or volume (including any other previously applied individual layers of the coating material located between the individual layers and the outer surface of the core).

10. The method according to any one of claims 1 to 9, wherein the coating material of one or more individual layers comprises one or more inorganic materials.

11. The method according to claim 10, wherein the coating material comprises one or more metal-containing or metalloid-containing compounds.

12. The method according to claim 11, wherein the compound comprises a hydroxide and / or an oxide.

13. The method according to claim 11 or 12, wherein the one or more coating materials include aluminum oxide, titanium dioxide, zinc sulfide, and / or zinc oxide.

14. The method according to claim 13, wherein the one or more coating materials include zinc oxide.

15. The method according to any one of claims 1 to 14, comprising applying the separate layers of the coating material to a core and / or a previously coated core by atomic layer deposition.

16. The method according to claim 15, wherein the mechanical sieving includes vibration or shaking of the sieve.

17. The method according to claim 16, wherein the mechanical sieving includes ultrasonic sieving.

18. The method according to any one of claims 1 to 17, further comprising the step of resuspending the separated particles in a solvent, with or without the presence of one or more pharmaceutically acceptable excipients.

19. The method according to any one of claims 2 to 18, wherein the biologically active agent is an anticancer agent.

20. The method according to claim 19, wherein the biologically active agent is azacitidine.

21. The method according to any one of claims 1 to 19, wherein the biologically active agent is selected from cytokines, peptide mimetic drugs, peptides, proteins, toxoids, serum, antibodies, vaccines, nucleosides, nucleotides, parts of genetic material, nucleic acids, or a mixture thereof.

22. The method according to any one of claims 1 to 18 and 21, wherein the biologically active agent is a peptide.

23. The method according to any one of claims 1 to 18 and 21, wherein the biologically active agent is a toxoid.

24. The method according to any one of claims 1 to 18, wherein the biologically active agent is a vaccine.

25. The method according to any one of claims 1 to 18 and 21, wherein the biologically active agent is a part of the genetic material.

26. The method according to any one of claims 1 to 18 and 21, wherein the biologically active agent is a nucleic acid.

27. The method according to any one of claims 1 to 18 and 21, wherein the biologically active agent is an anti-obesity agent and / or an anti-diabetic agent.

28. The method according to any one of claims 3 to 19 and 21, wherein the pharmaceutically acceptable excipient is a sugar or a sugar alcohol, and the biologically active agent is a polymer complex.

29. The method according to claim 28, wherein the polymer complex is selected from a peptide, a protein, and a portion of genetic material.

30. The method according to claim 28 or 29, wherein the polymer complex is a vaccine.

31. A composition obtained by a method defined in any one of claims 1 to 30.

32. The composition according to claim 31 for use in medical or veterinary practice.

33. A pharmaceutical formulation comprising the composition defined in claim 31 and a pharmaceutically acceptable adjuvant, diluent, or carrier.

34. The formulation according to claim 33, in the form of a sterile, injectable and / or injectable dosage form.

35. The formulation according to claim 33 or 34, in the form of a liquid, sol, or gel, which can be administered via a surgical administration device that forms a depot formulation.

36. A veterinary formulation comprising the composition defined in claim 31 and a veterinarily acceptable adjuvant, diluent, or carrier.

37. The formulation according to claim 36, in the form of a sterile, injectable and / or injectable dosage form.

38. The formulation according to claim 36 or 37, in the form of a liquid, sol, or gel, which can be administered via a surgical administration device that forms a depot formulation.

39. A method for preparing a formulation as defined in any one of claims 33 to 35, comprising mixing the composition defined in claim 31 with the pharmaceutically acceptable adjuvant, diluent, or carrier.

40. A method for preparing a formulation as defined in any one of claims 36 to 38, comprising mixing the composition defined in claim 31 with the veterinarily acceptable adjuvant, diluent, or carrier.

41. The composition according to claim 31 for use in the treatment of cancer.

42. The composition for use according to claim 41, wherein the cancer is one or more of myelodysplastic syndromes or their subtypes.

43. A preparation according to any one of claims 33 to 35, for use in the treatment of cancer.

44. The formulation for use according to claim 43, wherein the cancer is one or more of myelodysplastic syndromes or their subtypes.

45. The composition according to claim 31 for use in the treatment of obesity and / or diabetes.

46. A formulation according to any one of claims 33 to 35 for use in the treatment of obesity and / or diabetes.

Images