NEW PROCESS FOR THE MANUFACTURE OF PHARMACEUTICAL COMPOSITIONS

Abstract

There is provided a process for the preparation of composition in the form of a plurality of particles having a weight-, number-, and/or volume-based mean diameter that is between amount 10 nm and about 700 μm, which particles comprise: (a) solid cores, preferably comprising a biologically active agent; and (b) two or more sequentially applied, discrete layers, each of which comprises at least one separately applied coating material, and which two or more layers together surround, enclose and/or encapsulate said cores, which process comprises the sequential steps of: (1) applying an initial layer of at least one coating material to said solid cores by way of a gas phase deposition technique; (2) discharging the coated particles from the gas phase deposition reactor and subjecting the coated particles to agitation to disaggregate particle aggregates formed during step (1) by way of mechanical sieving technique; (3) reintroducing the disaggregated, coated particles from step (2) into the gas phase deposition reactor and applying a further layer of at least one coating material to the reintroduced particles; and (1) optionally repeating steps (2) and (3) one or more times to increase the total thickness of the at least one coating material that enclose(s) said solid core. The gas phase deposition technique is preferably atomic layer deposition. When the cores comprise biologically active agent, the compositions may provide for the delayed or sustained release of said active agent without a burst effect.

Claims

1. A process for the preparation of composition in the form of a plurality of particles having a weight-, number-, and/or volume-based mean diameter that is between amount 10 nm and about 700 μm, which particles comprise: (a) solid cores; and (b) two or more sequentially applied, discrete layers, each of which comprises at least one separate coating material, and which two or more layers together surround, enclose and/or encapsulate said cores, which process comprises the sequential steps of: (1) applying an initial layer of at least one coating material to said solid cores by way of a gas phase deposition technique; (2) discharging the coated particles from the gas phase deposition reactor and subjecting the coated particles to agitation to disaggregate particle aggregates formed during step (1) by way of mechanical sieving technique; (3) reintroducing the disaggregated, coated particles from step (2) into the gas phase deposition reactor and applying a further layer of at least one coating material to the reintroduced particles; and (4) optionally repeating steps (2) and (3) one or more times to increase the total thickness of the at least one coating material that enclose(s) said solid core.

2. The process as claimed in claim 1, wherein the cores comprise a biologically active agent and/or a pharmaceutically-acceptable excipient.

3. The process as claimed in claim 2, wherein the carrier/excipient material is a sugar or a sugar alcohol and/or is a pH modifying agent.

4. The process as claimed in claim 1, wherein the cores consist essentially of biologically active agent.

5. The process as claimed in claim 1, wherein the biologically active agent is selected from an analgesic, an anaesthetic, an anti-ADHD agent, an anorectic agent, an antiaddictive agent, an antibacterial agent, an antimicrobial agent, an antifungal agent, an antiviral agent, an antiparasitic agent, an antiprotozoal agent, an anthelmintic, an ectoparasiticide, a vaccine, an anticancer agent, an antimetabolite, an alkylating agent, an antineoplastic agent, a topoisomerase, an immunomodulator, an immunostimulant, an immunosuppressant, an anabolic steroid, an anticoagulant agent, an antiplatelet agent, an anticonvulsant agent, an antidementia agent, an antidepressant agent, an antidote, an antihyperlipidemic agent, an antigout agent, an antimalarial, an antimigraine agent, an anti-inflammatory agent, an antiparkinson agent, an antipruritic agent, an antipsoriatic agent, an antiemetic, an anti-obesity agent, an anthelmintic, an antiasthma agent, an antibiotic, an antidiabetic agent, an antiepileptic, an antifibrinolytic agent, an antihemorrhagic agent, an antihistamine, an antitussive, an antihypertensive agent, an antimuscarinic agent, an antimycobacterial agent, an antioxidant agent, an antipsychotic agent, an antipyretic, an antirheumatic agent, an antiarrhythmic agent, an anxiolytic agent, an aphrodisiac, a cardiac glycoside, a cardiac stimulant, an entheogen, an entactogen, an euphoriant, an orexigenic, an antithyroid agent, an anxiolytic sedative, a hypnotic, a neuroleptic, an astringent, a bacteriostatic agent, a beta blocker, a calcium channel blocker, an ACE inhibitor, an angiotensin II receptor antagonist, a renin inhibitor, a beta-adrenoceptor blocking agent, a blood product, a blood substitute, a bronchodilator, a cardiac inotropic agent, a chemotherapeutic, a coagulant, a corticosteroid, a cough suppressant, a diuretic, a deliriant, an expectorant, a fertility agent, a sex hormone, a mood stabilizer, a mucolytic, a neuroprotective, a nootropic, a neurotoxin, a dopaminergic, an antiparkinsonian agent, a free radical scavenging agent, a growth factor, a fibrate, a bile acid sequestrants, a cicatrizant, a glucocorticoid, a mineralcorticoid, a haemostatic, a hallucinogen, a hypothalamic-pituitary hormone, an immunological agent, a laxative agent, a antidiarrhoeals agent, a lipid regulating agent, a muscle relaxant, a parasympathomimetic, a parathyroid calcitonin, a serenic, a statin, a stimulant, a wakefulness-promoting agent, a decongestant, a dietary mineral, a biphosphonate, a cough medicine, an ophthamological, an ontological, a H1 antagonist, a H2 antagonist, a proton pump inhibitor, a prostaglandin, a radio-pharmaceutical, a hormone, a sedative, an anti-allergic agent, an appetite stimulant, a steroid, a sympathomimetic, a thrombolytic, a thyroid agent, a vasodilator, a xanthine, an erectile dysfunction improvement agent, a gastrointestinal agent, a histamine receptor antagonist, a keratolytic, an antianginal agent, a non-steroidal antiinflammatory agent, a COX-2 inhibitor, a leukotriene inhibitor, a macrolide, a NSAID, a nutritional agent, an opioid analgesic, an opioid antagonist, a potassium channel activator, a protease inhibitor, an antiosteoporosis agent, a cognition enhancer, an antiurinary incontinence agent, a nutritional oil, an antibenign prostate hypertrophy agent, an essential fatty acid, a non-essential fatty acid, a cytokine, a peptidomimetic, a peptide, a protein, a radiopharmaceutical, a senotherapeutic, a toxoid, a serum, an antibody, a nucleoside, a nucleotide, a vitamin, a portion of genetic material, a nucleic acid, or a mixture of any of these.

6. The process as claimed in claim 1, wherein the weight-, number-, or volume-, based mean diameter of the cores is between amount 1 μm and about 50 μm.

7. The process as claimed in claim 1, wherein between 3 and 10 discrete layers of coating material are applied to the core sequentially.

8. The process as claimed in claim 1, wherein, the total thickness of the discrete layers of coating material is between about 0.5 nm and about 2 μm.

9. The process as claimed in claim 1, wherein the maximum thickness of an individual discrete layer of coating material is about 1 hundredth of the weight-, number-, or volume-based mean diameter of the core, including any other previously-applied discrete layers of coating material that are located between said individual discrete layer and the outer surface of the core.

10. The process as claimed in claim 1, wherein the coating materials of the one or more discrete layers comprise one or more inorganic coating materials.

11. The process as claimed in claim 10, wherein the coating materials comprise one or more metal-containing, or metalloid-containing, compounds.

12. The process as claimed in claim 10, wherein the compounds comprise a hydroxide and/or an oxide.

13. The process as claimed in claim 10, wherein the one or more coating materials comprise aluminium oxide, titanium dioxide, zinc sulphide and/or zinc oxide.

14. The process as claimed in claim 10, wherein the one or more coating material comprise zinc oxide.

15. The process as claimed in claim 1, which comprises applying the separate layers of coating materials to cores, and/or previously-coated cores, by atomic layer deposition.

16. The process as claimed in claim 15, wherein the mechanical sieving comprises vibration or shaking of the sieve.

17. The process as claimed in claim 15, wherein the mechanical sieving comprises sonic sifting.

18. The process as claimed in claim 1, which process comprises a further step of resuspending separated particles in a solvent, with or without the presence of one or more pharmaceutically acceptable excipients.

19. The process as claimed in claim 2, wherein the biologically-active agent is an anti-cancer agent.

20. The process as claimed in claim 2, wherein the biologically-active agent is azacitidine.

21. A composition obtainable by way of a process as defined in claim 1.

22. (canceled)

23. A pharmaceutical or veterinary formulation comprising a composition as defined in claim 21 and a pharmaceutically-acceptable or a veterinarily-acceptable adjuvant, diluent or carrier.

24. The formulation as claimed claim 23 in the form of a sterile injectable and/or infusible dosage form.

25. The formulation as claimed or claim 24 in the form of a liquid, a sol or a gel, administrable via a surgical administration apparatus that forms a depot formulation.

26. A process as for the preparation of a formulation as defined in claim 23, which comprises admixing the composition as defined in with the relevant pharmaceutically-acceptable or veterinarily-acceptable adjuvant, diluent or carrier.

27-28. (canceled)

29. A method of treatment of cancer, which method comprises administration of a composition as claimed in claim 21, in which the biologically active agent is an anti-cancer agent, to patient in need of such treatment.

30. (canceled)

31. A method of treatment of cancer, which method comprises administration of a formulation as claimed in claim 23, in which the biologically active agent is an anti-cancer agent, to patient in need of such treatment.

Description

EXAMPLES

Comparative Example 1

[0142] Coated Azacitidine Microparticles I

[0143] Microparticles of azacitidine (Olon SpA, Rodano, Italy) were prepared by jet-milling (by Catalent, in Malvern, Pa. (USA)). The mean diameter of the jet-milled azacitidine particles was 1.2 μm as determined by laser diffraction (Sympatec, Helos (H1672) and Rodos, R3, Clausthal-Zellerfeld, Germany).

[0144] The powder was loaded to an ALD reactor (Picosun, SUNALE™ R-series, Espoo, Finland). 35 ALD cycles were performed at a reactor temperature of 50° C. Diethyl zinc and water were used as precursors, forming a first layer of zinc oxide. The first layer was about 5 nm in thickness (as estimated from the number of ALD cycles).

[0145] The powder was removed from the reactor and deagglomerated by means of forcing the powder through a metal sieve with a 20 μm mesh size using a rubber spatula.

[0146] The resultant deagglomerated powder was re-loaded into the ALD reactor and further 35 ALD cycles were performed as before forming a second layer of zinc oxide, extracted from the reactor and deagglomerated by means of manual sieving as above, reloaded to form a third layer, deagglomerated and the reloaded to a final, fourth layer.

[0147] To determine the drug load (i.e. w/w % of azacitidine in the powder), HPLC (Prominence-i (Shimadzu, Japan) equipped with a diode array detector (Shimadzu, Japan) set at 210 nm was employed using a 4.6×250 mm, 3 μm particles, C18 column (Luna, Phenomenex, USA)). The nanoshell coatings were dissolved in 1 M phosphoric acid and the slurry was diluted to dissolve the azacitidine by dilution with 1 g/L of sodium bisulfite in water, before filtration (0.2 μm RC, Lab Logistics Group, Germany) and further analyzed with HPLC (n=2). The drug load was determined as 64.7%.

Example 1

[0148] Coated Azacitidine Microparticles II

[0149] Corresponding coated microparticles of azacitidine were prepared as described in Comparative Example 1 above with the exception that the powder was sourced from MSN Labs (India), the particles had a mean diameter of 5.5 μm (as determined by laser diffraction (Shimadzu, SALD-7500nano, Kyoto, Japan), and deagglomeration was carried out by sieving through a nylon sieve with a mesh size of 20 μm using a sonic sifter (Tsutsui Scientific Instruments Co., Ltd., SW-20AT, Tokyo, Japan) to shake the powder through the sieve. The drug load was determined as 74.5%

Example 2

[0150] In Vitro Drug Release

[0151] In vitro release studies for the particles of Comparative Example 1 and Example 1 were conducted using a Sotax CE 7smart USP 4 apparatus (Sotax AG, Switzerland) linked to a CP 7-35 piston pump (Sotax AG, Switzerland) and a C613 fraction collector (Sotax AG, Switzerland).

[0152] Flow-through cells with a 22.6 mm diameter were prepared with a 5 mm ruby bead in the tip of the cell cone, in which the suspended samples were introduced.

[0153] The samples were analyzed in duplicates with a sample amount corresponding to 50 mg azacitidine per cell. The samples (33.3 mg azacitidine/mL) were dispersed by vortexing in 0.1% Tween 20+0.25% Na-CMC in saline (0.9% NaCl) phosphate buffer with a pH of 7.2.

[0154] The apparatus was used in an open-loop set-up, in which fresh 20 mM PIPES, pH 7.2 dissolution medium was continuously introduced into the system. The temperature of the water bath was set at 37° C.±0.5° C. and the flow rate of media was set at 16 mL/min. The medium was filtered before leaving the flow through cells using two Whatman glass microfiber filters, GF/F and GF/D (d=25 mm, Sigma-Aldrich/Merck KGaA, Germany). The collected fractions of the release medium were analyzed for azacitidine content using HPLC, using the same setup as was used for the drug load analysis described above.

[0155] FIGS. 3 and 4 show the respective azacitidine release profiles (percentage of azacitidine released per minute versus sampling time in the Sotax apparatus for samples obtained by Comparative Example 1, and Example 1, respectively.

[0156] It can be seen that Comparative Example 1 has a higher initial (burst) release than Example 1.