Patent 6,913,761

A pharmaceutical and/or veterinary formulation comprising about 2-30% (w/w) (on an active basis) of at least one active agent, about 0.5-20.0% (w/w) of a pore-foaming agent and the balance stearin. Such formulations provided release of the at least one active agent in humans and other animals for periods of 7 days up to about 2 years.

SUMMARY OF THE INVENTION

Thus, in a first aspect, the present invention provides a pharmaceutical and/or veterinary formulation comprising about 2-30% (w/w) (on an active basis) of at least one active agent, about 0.5-20.0% (w/w) of a pore-forming agent and the balance stearin.

In a preferred embodiment, the formulation comprises about 5-10% (w/w) (on an active basis) of at least one active agent, about 1.0-10.0% (w/w) of a pore-forming agent and the balance stearin.

In a more preferred embodiment, the formulation comprises about 5-10% (w/w) (on an active basis) of at least one active agent, about 2.0-5.0% (w/w) of a pore-forming agent and the balance stearin.

In a second aspect, the present invention provides a method of treating a disease or condition in a human or other animal, the method comprising administering to the human or other animal the formulation of the first aspect of the invention.

DETAILED DISCLOSURE OF THE INVENTION

The at least one active agent utilised in the formulation of the present invention, may be selected from agents having pharmaceutical or veterinary significance and may be any or a combination of peptides (e.g. hormones and antigens), polypeptides and proteins, and nucleic acid compounds and derivatives such as DNA and RNA.

Preferred active agents include:

(1) GnRH Agonists

Particularly preferred GnRH peptide agonists are deslorelin (described in U.S. Pat. No. 4,218,439), eulexin (described in FR7923545, WO 86/01105 and PT100899), goserelin (described in U.S. Pat. Nos. 4,100,274, 4,128,638, GB9112859 and GB9112825), leuprolide (described in U.S. Pat. Nos. 4,490,291, 3,972,859, 4,008,209, 4,005,063, DE2509783 and U.S. Pat. No. 4,992,421), dioxalan derivatives such as are described in EP 413209, triptorelin (described in U.S. Pat. Nos. 4,010,125, 4,018,726, 4,024,121, EP 364819 and U.S. Pat. No. 5,258,492), meterelin (described in EP 23004), buserelin (described in U.S. Pat. Nos. 4,003,884, 4,118,463 and 4,275,001), histrelin (described in EP217859), nafarelin (described in U.S. Pat. No. 4,234,571, WO93/15722 and EP52510), lutrelin (described in U.S. Pat. No. 4,089,946), leuprorelin (described in Plosker et al., Drugs 48 930-967, 1994) and LHRH analogues such as are described in EP181236, U.S. Pat. Nos. 4,608,251, 4,656,247, 4,642,332, 4,010,149, 3,992,365 and 4,010,149. The disclosures of each the patent specifications and papers referred to above are incorporated herein by reference.

The most preferred GnRH agonists are goserelin, deslorelin, leuprorelin, triptorelin, meterelin, buserelin, histrelin, nafarelin and combinations thereof. The formulae of these compounds are provided below:

	Goserelin C₅₉H₆₄N₁₈O₁₄C₂H₄O₂ D-Ser(Bu^t)⁶Azgly¹⁰-LHRH Acetate 3-[5- oxo-L-prolyl-L-tryptophyl-L-seryl-L-tyrosyl-(3-O-tert-butyl)-D-seryl-L-leucyl- L-arginyl-L-prolyl] cabazamide acetate.
	Deslorelin 6-D-tryptophan-9-(N-ethyl-L prolinamide)-10-deglycinamide P Glutamine-Histidine-Tryptophan-Serine-Tyrosine-D Tryptophan-Leucine- Arginine-Proline-ethylamide.
	Leuprorelin C₅₉H₆₄N₁₆O₁₂, C₂H₄O₂ Leuprorelin Acetate 5-oxo-L-prolyl-L- histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-arginyl-N-ethyl-L- prolinamide acetate.
	Triptorelin C₅₉H₆₄N₁₀O₁₂, C₂H₄O₂ D-TRp⁶-LHRH 5-oxo-L-prolyl-L-histidyl- L-tryptophyl-L-seryl-L-tyrosyl-D-tryptophyl-L-leucyl-L-arginyl-L- prolylglycinamide.
	Meterelin Des Gly^10-2-methyl-D-Trp⁶-Pro-ethyl-amide⁹LHRH.
	Buserelin C₅₀H₆₆N₁₆O₁₃, C₂H₄O₂ D-Ser(Bu^t)⁶-Pro9-NEt LHRH Acetate Oxo-L-prolyl-L-histidyl L-tryptophyl-L-seryl-L-tyrosyl-O-tert-butyl-D-seryl-L- leucyl-L-arginyl-N-ethyl-L-prolinamide acetate.
	Histrelin Pro-His-Trp-Ser-Tyr-Leu-D(N-benzyl) His-Arg-Pro-N-ethylamide.
	Nafarelin C₈₆H₆₃N₁₇O₁₃, xC₂H₄O₂yH₂OOxo-L-prolyl-L-histidyl-L-tryptophyl- L-seryl-L-tyrosyl-3-[2-naphthyl]-D-alanyl-L-leucyl-L-arginyl-N-ethyl-L- prolylglycinaminde acetate hydrate.

Formulations according to the invention which include a GnRH agonist as the at least one active agent may be used for controlling reproductive function or for the treatment of any disease or condition wherein reduction of sex hormone (i.e. testosterone or estradiol) levels over a prolonged period is beneficial. Examples include prostrate cancer, ovarian and breast cancer, benign hormone-dependent disorders such as endometriosis, myoma and premenstrual tension, uterine fibroids, induction of eudometrial atrophy prior to surgery, suppression of germ cell activity in chemotherapy, hirsutism, cyclic auditory dysfunction, porphyria and precocious puberty in children, benign prostatic hypertension in dogs and for use in other conditions where castration is known to have a beneficial clinical effect, including restoration of T cell-mediated immunity,

(2) GnRH Antagonists

Particularly preferred GnRH antagonists are ramorelix (L-prolone,1-(NZ-(N-(N-(N-
(N-(N-(N-(N-acetyl-3-(2-naphhthalenyl) -D-alanyl)-4-chloro-D-phenylalanyl)-D-
tryptophyl)-L-seryl) -L-tyrosyl-O-(6-deoxy-alpha-L-mannopyranosyl)-D-seryl)-L-
leucyl)-L-arginyl)-2-(aminoacrbonyl) hyrazide, teverelix (D-alaninamide,N-acetyl-3-(2-
naphthalenyl) -D-alayl-4-chloro-pheuylalanyl-3-(3-pyridinyl) -D-alanyl-L-seryl-L-
tyrosyl-N6-(aminocarbonyl)-D-lysyl-L-leucyl-N6-(1-methylethyl)-L-lysyl-L-prolyl, cetrorelix (D-Alaninamode, N-acetyl-3-(2-naphthalenyl)-D-alanyl-4-chloro-D-
phenylalanyl-3-(3-pyridinyl)-D-alanyl-L-seryl-L-tyrosyl-N5-(aminocarbonyl)-D-ol-L-
leucyl-L-arginyl-L-prolyl, ganirelix (N-Ac-D-Nal,D-pCl-Phe,D-
Pal,DhArg(Et)2,hArg(Et)2,D-Ala) GnRH, alanex, abarelix (D-Alaninamide,N-acetyl-3-
(2-naphthalenyl)-D-alanyl-4-chloro-D-phenylalanyl-3-(3-pyridinyl)-D-alanyl-L-seryl-
N-methyl-L-tryosyl-D-asparainyl-L-leucyl-N6-(1-methylethyl)-L-lysyl-L-prolyl; N-
(S)-tetrahydrofuroyl-Gly-D2Nal-D4Ciphe-D3Pal-Ser-NmeTyr-D-lys(Nic)-Leu-
Lys(Isp)-Pro-D-Ala-NH2; isopropyl-13-(N-benzyl-N-methaminomethyl)-7-(2,6-
diflurobenzyl)-4,7-dihydro-2-(4-isobutyrylaminophenyl)-4-oxothieno(2,3-b))pyridine-
5-carboxyatehydrochloride). Other preferred GnRH antagonists are described in U.S. Pat. Nos. 5,110,904, 5,300,492, 5,807,983, 5,169,932, 5,296,468 and 5,502,035.

(3) Somatostatin Analogues

Particularly preferred somatostatin analogues include somatostatin-14, octreotide, lanreotide and angiopeptin cyclopeptides (U.S. Pat. No. 5,569,647).

Formulations according to the invention which include a somatostatin analogue as the at least one active agent may be used for treating, for example, hyperinsulinaemia and peptic ulcers.

(4) Lipid Lowering Agents

Particularly preferred lipid lowering agents include compounds which Inhibit HMG CoA reductase such as cerevastatin, mevastatin, simvastatin, pravastatin and lovastatin.

Formulations according to the invention which includes these agents may be used for treating, for example, hyperlipoproteineamia.

(5) Cyclosporins

Preferred cyclosporins include naturally occurring cyclosporins (e.g. as described by Dreyfuss et al., (1976) Europ. J. Appl. Microbiol. Vol. 3: 125-133), and analogues (e.g. as described by Wenger R. M. (1982), Chemistry of Cyclosporin A in "Cyclosporin "A", White D. G. G. ed., Amsterdam; Elsevier).

Formulations according to the invention which include a cyclosporin or cyclosporin analogue as the at least one active agent may be used, for example, as immunosuppressive agents for prophylaxis and treatment of organ rejection in allogenieic transplants.

(6) Angiotensin Converting Enzyme Inhibitors

Preferred ACE inhibitors include captopril, enalapril, trandolaprilate, perindoprilate, quinaprilate, fasidotril, omapatrilate and lisinopril.

Formulations according to the invention which include such agents may be used, for example, as antihypertensives.

(7) Calcitonins

Preferred calcitonins include human, salmon, and porcine calcitonin. Analogues of these polypeptides may also be suitable.

Formulations according to the invention which include calcitonin or calcitonin analogues may be used for treatment of, for example, hypercalcemia and for decreasing concentrations of phosphate in patients suffering from hyperparathyroidism, vitamin D intoxication, and osteolytic bone metastases.

(8) Substance P Antagonists

Preferred substance P antagonists include fragment 4-11 (i.e. Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH₂ and variant forms), fragment 5-11 (i.e. Gln-Gln-Phe-Phe-Gly-Leu-Met-NH₂and variant forms), fragment 6-11 (i.e. Gln-Phe-Phe-Gly-Leu-Met-NH₂and variant forms), fragment 7-11 (i.e. Phe-Phe-Gly-Leu-Met-NH₂), fragment 8-11 (i.e. Phe-Gly-Leu-Met-NH₂) and fragment 9-11 (i.e. Gly-Leu-Met-NH₂). Other suitable substance P antagonists include those described in the present applicant's co-pending Australian Provisional Patent Application No. PP9008.

Formulations according to the invention which include substance P antagonists may be used for treatment of cancer including chemotherapy-induced nausea and vomiting, pain, allergy, asthma, inflammatory conditions including inflammatory bowel disease and depression.

(9) Painkillers

Preferred painkillers include opioids such as morphine, levorphanol and meperidine (pethidine), and amide local anaesthetics such as bupivacaine, lidocaine, etidocaine and mepivacaine.

Formulations according to the invention which include such painkilling agents may be used to treat acute pain (e.g. such as that experienced by hip replacement patients) or chronic regional pain.

(10) Opioid Antagonists

Preferred opioid antagonists include naltrexone, naloxone and methadone.

Formulations according to the invention which include opioid antagonists may be used for treatment of opioid dependency.

(11) Anti-depressants

Preferred anti-depressants include venlafaxine, triflupromazine, methotrimeprazine, promethazine, buspirone, gepirone and fluoxetine (Prozac).

(12) Non-steroidal Anti-inflammatory Agents

Preferred non-steroidal anti-inflammatory agents include naproxen sodium indomethacin, sulindac, tolmelin, acemetacin, zomepirac, mefenamic acid, fenoprofen, flufenamic acid, phenylbutazone, flurbiprofen, ketoprofen and axsain.

Formulations according to the invention which include non-steroidal anti-inflammatory agents may be used for the treatment of post-operative inflammation and inflammation associated with, for example, rheumatoid arthritis.

(13) Miscellaneous

Other suitable active agents include paroxetine for treatment of social anxiety disorder/social phobia, galanin antagonists such as galanin fragment 1-13-Pro-Pro-Ala-Leu-Ala-Leu-Ala amide and galanin (1-13)-spantide 1 for treatment of obesity, eating disorders, depression and pain; activin and inhibin fragments such as α-subunit fragment 1-32 and β-fragment 67-94 for fertility control; adrenocorticotropic hormone (ACTH) and variants and fragments for treatment of West Syndrome and infantile spasms; growth hormone and its analogues for replacement therapy in growth-hormone deficient children; erythropoietin (EPO) and its analogues for treatment of anaemia; endothelin antagonists for prevention of congestive heart failure, prevention of acute renal failure and subarachnoid haemorrhage, prevention and treatment of atherosclerosis, treatment of hypertension, prevention of stroke and treatment of chronic obstructive pulmonary disease; leptin and its agonists and antagonists for treatment of obesity and eating disorders such as anorexia nervosa, and for weight loss; thyrotropin releasing hormone (TRH) and its analogues (e.g. pGlu-His-Pro-Gly) for treatment of, for example, epilepsy; and theophylline and its analogues for the treatment of asthma, systemic capillary leak syndrome and Parkinson's disease. Vaccine antigens, including DNA encoding vaccine antigens, may also be delivered in a formulation according to the present invention.

Formulations according to the invention may include a combination of active agents. Examples of preferred combinations (comprising "Agent 1" and "Agent 2") are shown in Table 1.

TABLE 1
Agent 1	Agent 2
HMG Co A reductase inhibitor	Gemfibrozil
Non-steroidal anti-inflammatory agent	Mycophenolate mofelil
GnRH agonist	Trk tyrosine inhibitor
GnRH agonist	Testosterone
Calcitonin	Estrogen
Calcitonin	Etridonate
Calcitonin	Pamridonate
Octreotide	α-interferon
Octreotide	IGF-1
Octreotide	Miclodrine
GnRH agonist	Flutamide
Etofylline	Theophylline

Preferably, the at least one active agent is/are of low to moderate lipophilicity. More preferably, at least one active agent has a log octanol/water partition coefficient (log P) (Ruelle and Kesselring (1998), J Pharm Sci. Vol. 87:1115-24) in the range of 5.0 to -;3.0. Most preferred are active agents having a log P value in the range of 3.0 to -;3.0 and, particularly, those having a log P value in the range of 1.0 to -;3.0.

Log P values for representatives of the abovementioned classes of active agents are provided in Table 2.

TABLE 2
Agent	log octanol/water partition (log P)

octreotide	1.40
cyclosporin A	2.90
captopril	-;1.86
trandolaprilate	1.02
perindoprilate	-;0.36
quinaprilate	0.69
morphine	0.76
lidocaine	2.26
methadone	3.93
promethazine	4.75
indomethacin	4.27
flufenamic acid	1.14
phenylbutazone	3.16
theophylline	-;0.02
etofylline	0.35
TRH	<2.40

The pore-forming agent may be any agent or combination of agents which enables the sustained release of the at least one active agent from the stearin excipient, with the proviso that when the at least one active agent is a GnRH agonist(s) the pore-forming agent is not lecithin.

Preferably, the pore-forming agent or agents is/are selected from water-soluble agents such as inorganic salts (e.g. chlorides, phosphates and sulphates), organic salts (e.g. acetates, formates, propionates, glutamates, and aspartates), sugars (e.g. glucose, trehalose, mannose, galactose, sucrose and low molecular weight carbohydrates such as hydroxy propyl methylcellulose (HPMC) and carboxy methylcellulose (CMC)), aminosugars (e.g. glucosamine and galactosa mine), amino acids/peptides (e.g. lysine, arginine, glutamic acid, aspartic acid, carnosine and aspartame), water-soluble proteins and water-soluble vitamins (e.g. Vitamin B).

Presently, the most preferred pore-forming agent is lecithin (except where the at least one active agent is a GnRH agonist(s)) and the amino acid lysine. Lecithin is a mixture of diglycerides of stearic, palmitic and oleic acids linked to the choline ester of phosphoric acid. The efficacy of lecithin as a pore-forming agent in a sustained release formulation comprising deslorelin and stearin is described in International patent application No. PCT/AU96/00370 (WO 97/00093), the entire disclosure of which is incorporated herein by reference.

As will be evident from the examples herein, variation of the identity and/or amount of the pore-forming agent(s) utilised allows for the manipulation of the release profile of the active agent(s) to suit particular therapeutic uses.

The stearin excipient is preferably in a non-crystalline form. Stearin is partially hydrogenated palm oil having, as the principle fatty acids, C16:0(45%) and C18:0(53%). The melting point of stearin is about 60° C. It is believed that the use of stearin as the excipient contributes to the success of the formulations according to the invention, because it appears, surprisingly, to produce only a minimal to mild inflammatory response in a recipient resulting in the encapsulation of the formulation within a thin layer of fibroblasts. It will be appreciated by persons skilled in the art, that alternative formulations comprising excipient(s) with similar characteristics to those included in the formulation defined above in the first aspect may likewise provoke minimal to mild inflammatory responses and consequently be useful for the sustained-release of an active agent(s). Such alternative formulations are to be regarded as falling within the scope of the present invention.

The formulations according to the invention may be for administration to humans and other animals selected from dogs, cats, other domestic animals, and captive wildlife.

Typically, the formulations will release the active agent(s), in vitro, into phosphate buffered saline (PBS: pH 7.3, prepared by dissolving 8.00 g of sodium chloride, 1.00 g di-sodium hydrogen phosphate anhydrous, 0.40 g sodium dihydrogen phosphate dihydrate (0.31 g if anhydrous), and 0.05 g sodium azide in 1 litre of deionised water), at 37° C. at a rate of about 2-350 μg/day for at least 7 days and up to about 2 years.

Further, the formulations will typically exist as a depot formulation for example in the form of free flowing beads or rods which may have been extruded.

Extruded rods may be cut into predetermined lengths for implantation, by standard techniques, in a human or other animal. As will be readily appreciated, the length of the rod will determine the rate and dose of the active agent(s). As opposed to implanting longer rods more than one rod can be implanted in each human or other animal. Injection of a suspension of formulated particulate material such as free flowing beads may also deliver the active agent(s) at the desired rate and dose.

Formulations for administration as free flowing beads and/or implants, particularly to dogs, may be produced as follows:

Stearin (supplied as free flowing beads of 1 mm or less in diameter made by Vandenberg Foods) and pore-forming agent are mixed. The active agent may then be added and thoroughly mixed into the excipient and pore-forming agent mixture. This material may then be used for injection. Alternatively the mixture can be transferred to the barrel of a ram extruder that has a 1 mm nozzle attached and is equilibrated to 55° C. (or other temperature sufficient to soften the stearin). After attaching the ram, pressure (40 psi) is applied until the product begins to extrude. At this point the pressure can be backed off and the product allowed to reach 55° C. (or other temperature sufficient to soften the stearin). The product may then be extruded at, for example, a rate of 3 g over a 30 second period. The resulting extrudate is then allowed to cool and then broken up and re-extruded through a 1 mm nozzle to ensure uniformity of content throughout the mix. The 1 mm nozzle may then be replaced with a 2.3 mm diameter nozzle and the product extruded (using the same temperature equilibration procedure prior to extrusion). After cooling the long rods produced can be sectioned into lengths of the required weight and the sectioned lengths sterilised by gamma-irradiation.

Alternatively, formulations for administration as bioimplants, particularly for dogs, may be produced by:

Stearin and pore-forming agent are mixed. The active agent may then be added and thoroughly mixed into the excipient and pore-forming agent mixture. The mixture can then be transferred to the barrel of an extruder that has a 2.3 mm nozzle attached and which has been equilibrated to a temperature sufficient to soften the stearin. The extruder is started and the product begins to extrude and the extrudate is cut to length. The sectioned length can be terminally sterilised.

Further, in preparing formulations according to the present invention, especially where the at least one active agent is a peptide(s), polypeptide(s) or protein(s), it is preferred that the at least one active agent is firstly pre-treated with a process comprising at least two freeze drying steps. Such freeze drying steps may be conducted in accordance with any of the commonly known methods for freeze drying of proteinaceous materials. It is, however, preferred that the active agent(s) be freeze dried from a 5-50% (more preferably, 5-15%) (w/w) solution of the active agent(s) in a suitable solvent (e.g. an alcohol solution such as 30% (w/w) ethanol in water). The freeze dried active agent(s) may then be redissolved or homogenised in a suitable solvent (e.g. 25-75% (w/w) in a diluted weak acid solution such as 1-5% (w/w) acetic acid in water) and subsequently freeze dried again. Thus, the freeze drying of the active agent(s) may comprise the steps of;

(i) forming a 5-50% (w/w) solution of the active agent(s),

(ii) freeze drying said solution of step (i),

(iii) forming a 25-75% (w/w) solution or homogenate from said freeze dried active agent(s), and

(iv) freeze drying said solution or homogenate of step (iii).

Claim 1 of 40 Claims

1. A pharmaceutical and/or veterinary formulation comprising about 2-30% (w/w) (on an active basis) of at least one active agent, about 0.5-20.0% (w/w) of a pore-forming agent and the balance stearin, with the proviso that where the at least one active agent is a gonadotropin-releasing hormone(GnRH) agonist(s) the pore-forming agent is not lecithin.

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