INJECTABLE OIL-BASED PHARMACEUTICAL COMPOSITION

Abstract

There is provided a pharmaceutical or veterinary formulation comprising: (a) a plurality of particles having a weight-, number-, or volume-based mean diameter that is between amount 10 nm and about 700 μm, which particles comprise solid cores coated with zinc oxide; suspended in (b) an oleaginous carrier system comprising a pharmaceutically-acceptable or veterinarily-acceptable oil, which zinc oxide coated particles comprise: (1) solid cores comprising a biologically-active agent; (2) one or more discrete layers surrounding said cores, said one or more layers each comprising at least one separate zinc oxide coating. Said zinc oxide coated particles are preferably synthesized via a gas phase coating technique, such as atomic layer deposition. When the cores comprise biologically-active agent, and the particles are suspended in an oleaginous carrier system, the formulation may provide for the delayed or sustained release of said active agent without a burst effect.

Claims

1. A pharmaceutical or veterinary formulation comprising: (c) a plurality of particles having a weight-, number-, or volume-based mean diameter that is between amount 10 nm and about 700 μm, which particles comprise solid cores coated with zinc oxide; suspended in (d) an oleaginous carrier system comprising a pharmaceutically-acceptable or veterinarily-acceptable oil.

2. A formulation as claimed in claim 1, wherein the zinc oxide-coated particles comprise: (a) solid cores comprising a biologically-active agent; (b) one or more discrete layers surrounding said cores, said one or more layers each comprising at least one separate zinc oxide coating.

3. A formulation as claimed in claim 2, wherein the cores consist essentially of a biologically-active agent.

4. A formulation as claimed in claim 3, 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 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.

5. A formulation as claimed in claim 4, wherein the biologically-active agent is azacitidine.

6. A formulation as claimed in any one of the preceding claims, wherein the weight-, number-, or volume-based mean diameter of the particles is between amount 1 μm and about 50 μm.

7. A formulation as claimed in any one of the preceding claims, wherein more than one discrete layer of zinc oxide is applied to the core sequentially.

8. A formulation as claimed in claim 7, wherein between 3 and 10 discrete layers of zinc oxide are applied.

9. A formulation as claimed in any one of the preceding claims, wherein the total thickness of the zinc oxide coating is between about 0.5 nm and about 2 μm.

10. A formulation as claimed in any one of claims 7 to 9, wherein the maximum thickness of an individual discrete layer of zinc oxide coating is about 1 hundredth of the weight-, number-, or volume-based mean diameter of the core, including any other discrete layers that have previously been applied to the core.

11. A formulation as claimed in any of the preceding claims, wherein the carrier system comprises one or more medium chain triglycerides.

12. A formulation as claimed in claim 11, wherein the medium chain triglycerides comprise C.sub.6 to C.sub.12 alkyl chain triglycerides.

13. A formulation as claimed in any one of the preceding claims in the form of a sterile injectable and/or infusible dosage form.

14. A formulation as claimed in claim 13 in the form of a liquid, a sol or a gel, administrable via a surgical administration apparatus that forms a depot formulation.

15. A process for the preparation of a formulation as defined in any one of the preceding claims, wherein the coated particles are made by applying the layer(s) of zinc oxide coating material to the cores, and/or previously-coated cores, by atomic layer deposition.

16. A process as claimed in claim 15, wherein: (i) solid cores are coated with a first discrete layer of coating material; (ii) the coated cores from step (i) are then subjected to a deagglomeration process step; (iii) the deagglomerated coated cores from step (ii) are then coated with a second discrete layer of coating material; (iv) repeating steps (ii) and (iii) to obtain the required number of discrete layers.

17. A process as claimed in claim 16, wherein the deagglomeration step that takes place between applications of coatings comprises sieving.

13. A process as claimed in claim 17, wherein the sieving comprises sonic sifting.

19. A process for the preparation of a formulation as defined in any one of claims 1 to 14 wherein the coated particles are mixed with the carrier system after coating.

20. An injectable and/or infusible dosage form comprising a formulation as defined in any one of claims 1 to 14 contained within a reservoir and an injection or infusion means.

21. A dosage form as claimed in claim 20 which is a surgical administration apparatus that forms a depot formulation.

22. A dosage form as claimed in claim 20 or claim 21, wherein coated particles as defined in any one of claims 1 to 14 and the carrier system are housed separately, and in which admixing occurs prior to and/or during injection or infusion.

Description

EXAMPLES

Example 1

Coated Azacitidine Microparticles

[0128] Samples of microparticles of azacitidine (MSN Labs, India) were prepared by jet-milling. The mean diameter of the jet-milled azacitidine particles was 4 μm as determined by laser diffraction by the provider.

[0129] The powder was loaded to an ALD reactor (Picosun, SUNALE™ R-series, Espoo, Finland) where 30 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).

[0130] The powder was removed from the reactor and deagglomerated by means of forcing the powder through a polymeric sieve with a 20 μm mesh size using a sonic sifter.

[0131] The resultant deagglomerated powder was re-loaded into the ALD reactor and further 30 ALD cycles were performed as before forming a second layer of zinc oxide, extracted from the reactor and deagglomerated by means of sonic sifting as above, reloaded to form a third layer, deagglomerated and then reloaded to a final, fourth layer.

[0132] To determine the drug load (i.e. w/w % of azacitidine in the powder), HPLC (Prominence-i (Shirnadzu, 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 74%.

Example 2

In Vivo Drug Release of Suspensions

[0133] Two samples were prepared according to the procedure described below.

[0134] A first sample containing microparticles of azacitidine (prepared according to the process described in Example 1 above) was suspended in 0.1% (w/w) Polysorbate 20, 0.25% (w/w) sodium carboxylmethyl cellulose in a phosphate buffered saline solution (pH 7.4). A second sample containing microparticles of azacitidine was suspended in a medium chain triglycerides (Crodamol GTCC).

[0135] The concentration of microparticles of azacitidine in each formulation was adjusted to 13.5 mg/kg (body weight of the rats). The samples were prepared immediately prior to administration and were injected within 10 minutes of preparation.

[0136] The vials containing the samples were tapped at least 10 times to dislodge any material that may have settled at the bottom of the vial. The samples were diluted with 0.5 mL of a solution containing 0.1% (w/w) Polysorbate 20, 0.25% (w/w) sodium carboxylmethyl cellulose in a phosphate buffered saline solution (pH 7.4). The vials were then vortexed for 30 to 60 seconds and inverted. All vials were inverted 3 times just before each injection to avoid sedimentation of the sample.

[0137] Eight male Sprague Dawley rats were supplied by Charles River Laboratories (UK) where the testing took place.

[0138] The rats were randomly divided into two groups of four rats each and weighed between 294 to 327 g at the day of administration. The intended administration area was clipped free from hair prior to injection and the injection site was marked. Each animal was dosed via subcutaneous injection. For both groups, the formulation was drawn into a 1 mL BD syringe and the dose was administered through a 20G needle (BD microlance) into the flank. The injection site area was kept free from hair throughout the study.

[0139] Blood samples (ca 0.2 mL) were collected from the tail vein into K.sub.2EDTA (dipotassium ethylenediaminetetraacetic acid) tubes containing 5 μL THU (25 μL/mL blood; Tetrahydrouridine, which is a competitive cytidine deaminase inhibitor) stabilising agent (1 mg/mL aqueous solution) at the following time-points: 0.5, 1, 3, 6, 12, 24, 48, 72, 120 and 168 h. The blood samples collected were centrifuged (1500 g for 10 min at 4° C.) to separate the plasma, which was stored at −80° C. until analysis.

[0140] Bioanalysis was performed by Lablytica Life Science AB (an external contract research organization based in Uppsala) to determine the concentration of azacitidine in sodium heparin rat plasma using LC-MSMS.

[0141] FIG. 1 shows the respective release profile from the different samples. The dotted line shows the release profile for the sample suspended in 0.1% (w/w) Polysorbate 20, 0.25% (w/w) sodium carboxymethyl cellulose in a phosphate buffered saline solution (pH 7.4) and the solid line shows the release profile for the sample suspended in medium chain triglycerides.

[0142] It can be seen that the sample suspended in the phosphate buffered saline solution has a higher initial burst release than the sample suspended in medium chain triglycerides.