Nanoparticulate stabilized anti-hypertensive compositions

• US 20100028439A1
• Filed: 05/22/2006
• Published: 02/04/2010
• Est. Priority Date: 05/23/2005
• Status: Abandoned Application

• Current Assignee: Elan Pharma International Limited (Perrigo Company PLC)
• Original Assignee: Elan Pharma International Limited (Perrigo Company PLC)
• Inventors: Jenkins, Scott, Liversidge, Gary G.
• Application Number:
  US11/437,833
• Publication Number:
  US 20100028439A1
• Time in Patent Office: Days
• US Class Current: 424/489
• CPC Class Codes: A61K 31/554 having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives

Abstract

The present invention is directed to anti-hypertensive compositions comprising a nanoparticulate temocapril, or a salt or derivative thereof, having improved bioavailability. The nanoparticulate temocapril particles of the composition have an effective average particle size of less than about 2000 nm and are useful in the treatment of hypertension and related diseases.

Claims

1. A stable nanoparticulate anti-hypertensive pharmaceutical composition comprising:

(a) particles of a thiazepine compound having anti-hypertensive pharmaceutical properties and having an effective average particle size of less than 2000 nm; and

(b) at least one surface stabilizer.

2. The composition of claim 1, wherein the thiazepine is temocapril or a salt thereof.

3. The composition of claim 2 wherein the salt is the hydrochloride salt.

4. The composition of claim 1, wherein the thiazepine particle is in a crystalline phase, an amorphous phase, or a semi-crystalline phase.

5. The composition of claim 1, wherein the effective average particle size of the thiazepine particles is selected from the group consisting of less than 1900 nm, less than 1800 nm, less than 1700 nm, less than 1600 nm, less than 1500 nm, less than 1400 mm, less than 1300 nm, less than 1200 nm, less than 1100 nm, less than 1000 nm, less than 900 nm, less than 800 nm, less than 700 nm, less than 600 nm, less than 500 nm, less than 400 nm, less than 300 nm, less than 250 nm, less than 200 nm, less than 100 nm, less than 75 nm, and less than 50 nm.

6. The composition of claim 1, wherein the composition is formulated:

(a) for administration selected from the group consisting of parental injection, oral administration in solid, liquid, or aerosol form, vaginal, nasal, rectal, optically, ocular, local, buccal, intracisternal, intraperitoneal, and topical administration;

(b) into a dosage form selected from the group consisting of liquid dispersions, gels, sachets, solutions, aerosols, ointments, tablets, capsules, creams, and mixtures thereof.

(c) into a dosage form selected from the group consisting of controlled release formulations, fast melt formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, and mixed immediate release and controlled release formulations;

or

(d) any combination thereof.

7. The composition of claim 1, wherein the composition further comprises one or more pharmaceutically acceptable excipients, carriers, or a combination thereof.

8. The composition of claim 1, wherein:

(a) thiazepine is present in an amount consisting of from about 99.5% to about 0.001%, from about 95% to about 0.1%, and from about 90% to about 0.5%, by weight, based on the total combined weight of the thiazepine and at least one surface stabilizer, not including other excipients;

(b) at least one surface stabilizer is present in an amount of from about 0.5% to about 99.999% by weight, from about 5.0% to about 99.9% by weight, and from about 10% to about 99.5% by weight, based on the total combined dry weight of the thiazepine and at least one surface stabilizer, not including other excipients;

or

(c) a combination of (a) and (b).

9. The composition of claim 1, wherein the surface stabilizer is selected from the group consisting of an ionic surface stabilizer, an anionic surface stabilizer, a cationic surface stabilizer, a zwitterionic surface stabilizer, and a non-ionic surface stabilizer.

10. The composition of claim 1, wherein the surface stabilizer is selected from the group consisting of cetyl pyridinium chloride, gelatin, casein, phosphatides, dextran, glycerol, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, dodecyl trimethyl ammonium bromide, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, hydroxypropyl celluloses, hypromellose, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hypromellose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde, poloxamers;

poloxamines, a charged phospholipid, dioctylsulfosuccinate, dialkylesters of sodium sulfosuccinic acid, sodium lauryl sulfate, alkyl aryl polyether sulfonates, mixtures of sucrose stearate and sucrose distearate, p-isononylphenoxypoly-(glycidol), decanoyl-N-methylglucamide;

n-decyl β

-D-glucopyranoside;

n-decyl β

-D-maltopyranoside;

n-dodecyl P-D-glucopyranoside;

n-dodecyl β

-D-maltoside;

heptanoyl-N-methylglucamide;

n-heptyl-β

-D-glucopyranoside;

n-heptyl β

-D-thioglucoside;

n-hexyl β

-D-glucopyranoside;

nonanoyl-N-methylglucamide;

n-noyl β

-D-glucopyranoside;

octanoyl-N-methylglucamide;

n-octyl-β

-D-glucopyranoside;

octyl β

-D-thioglucopyranoside;

lysozyme, PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivative, PEG-vitamin A, PEG-vitamin E, lysozyme, random copolymers of vinyl acetate and vinyl pyrrolidone, a cationic polymer, a cationic biopolymer, a cationic polysaccharide, a cationic cellulosic, a cationic alginate, a cationic nonpolymeric compound, a cationic phospholipid, cationic lipids, polymethylmethacrylate trimethylammonium bromide, sulfonium compounds, polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate, hexadecyltrimethyl ammonium bromide, phosphonium compounds, quarternary ammonium compounds, benzyl-di(2-chloroethyl)ethylammonium bromide, coconut trimethyl ammonium chloride, coconut trimethyl ammonium bromide, coconut methyl dihydroxyethyl ammonium chloride, coconut methyl dihydroxyethyl ammonium bromide, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride bromide, C_12-15-dimethyl hydroxyethyl ammonium chloride, C_12-15-dimethyl hydroxyethyl ammonium chloride bromide, coconut dimethyl hydroxyethyl ammonium chloride, coconut dimethyl hydroxyethyl ammonium bromide, myristyl trimethyl ammonium methyl sulphate, lauryl dimethyl benzyl ammonium chloride, lauryl dimethyl benzyl ammonium bromide, lauryl dimethyl (ethenoxy)₄ ammonium chloride, lauryl dimethyl (ethenoxy)₄ ammonium bromide, N-alkyl (C_12-18)dimethylbenzyl ammonium chloride, N-alkyl (C_14-18)dimethyl-benzyl ammonium chloride, N-tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N-alkyl and (C_12-14) dimethyl 1-napthylmethyl ammonium chloride, trimethylammonium halide, alkyl-trimethylammonium salts, dialkyl-dimethylammonium salts, lauryl trimethyl ammonium chloride, ethoxylated alkyamidoalkyldialkylammonium salt, an ethoxylated trialkyl ammonium salt, dialkylbenzene dialkylammonium chloride, N-didecyldimethyl ammonium chloride, N-tetradecyldimethylbenzyl ammonium, chloride monohydrate, N-alkyl(C_12-14) dimethyl 1-naphthylmethyl ammonium chloride, dodecyldimethylbenzyl ammonium chloride, dialkyl benzenealkyl ammonium chloride, lauryl trimethyl ammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl benzyl dimethyl ammonium bromide, C₁₂ trimethyl ammonium bromides, C₁₅ trimethyl ammonium bromides, C₁₇ trimethyl ammonium bromides, dodecylbenzyl triethyl ammonium chloride, poly-diallyldimethylammonium chloride (DADMAC), dimethyl ammonium chlorides, alkyldimethylammonium halogenides, tricetyl methyl ammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyl trioctylammonium chloride, polyquaternium 10, tetrabutylammonium bromide, benzyl trimethylammonium bromide, choline esters, benzalkonium chloride, stearalkonium chloride compounds, cetyl pyridinium bromide, cetyl pyridinium chloride, halide salts of quaternized polyoxyethylalkylamines, quaternized ammonium salt polymers, alkyl pyridinium salts;

amines, amine salts, amine oxides, imide azolinium salts, protonated quaternary acrylamides, methylated quaternary polymers, and cationic guar.

11. The composition of claim 1, additionally comprising one or more active agents useful for the treatment of hypertension and related diseases.

12. The composition of claim 11, wherein the related disease is selected from the group consisting of ischemic heart disease, stroke, peripheral artery disease, hypertensive heart disease, and renal failure.

13. The composition of claim 11, wherein the one or more active agent is selected from the group consisting of diuretics, beta-blockers, ACE inhibitors, calcium channel blockers, alpha blockers, alpha-beta blockers, angiotensin antagonists, nervous system inhibitors, and vasodilators.

14. The composition of claim 1, wherein:

(a) upon administration to a mammal the thiazepine particles redisperse such that the particles have an effective average particle size selected from the group consisting of less than 2 microns, less than 1900 nm, less than 1800 nm, less than 1700 nm, less than 1600 nm, less than 1500 nm, less than 1400 nm, less than 1300 nm, less than 1200 nm, less than 1100 nm, less than 1000 nm, less than 900 nm, less than 800 nm, less than 700 nm, less than 600 nm, less than 500 nm, less than 400 nm, less than 300 nm, less than 250 nm, less than 200 nm, less than 150 nm, less than 100 nm, less than 75 nm, and less than 50 nm;

(b) the composition redisperses in a biorelevant media such that the thiazepine particles have an effective average particle size selected from the group consisting of less than 2 microns, less than 1900 nm, less than 1800 nm, less than 1700 nm, less than 1600 nm, less than 1500 nm, less than 1400 nm, less than 1300 nm, less than 1200 nm, less than 1100 nm, less than 1000 nm, less than 900 nm, less than 800 nm, less than 700 nm, less than 600 nm, less than 500 nm, less than 400 nm, less than 300 nm, less than 250 nm, less than 200 nm, less than 150 nm, less than 100 nm, less than 75 nm, and less than 50 nm;

or

(c) a combination of (a) and (b).

15. The composition of claim 14, wherein the biorelevant media is selected from the group consisting of water, aqueous electrolyte solutions, aqueous solutions of a salt, aqueous solutions of an acid, aqueous solutions of a base, and combinations thereof.

16. The composition of claim 1, wherein:

(a) the T_max of the thiazepine, when assayed in the plasma of a mammalian subject following administration, is less than the T_max for a non-nanoparticulate composition of the same thiazepine, administered at the same dosage;

(b) the C_max of the thiazepine, when assayed in the plasma of a mammalian subject following administration, is greater than the C_max for a non-nanoparticulate composition of the same thiazepine, administered at the same dosage;

(c) the AUC of the thiazepine, when assayed in the plasma of a mammalian subject following administration, is greater than the AUC for a non-nanoparticulate composition of the same thiazepine, administered at the same dosage;

or

(d) any combination thereof.

17. The composition of claim 16, wherein:

(a) the T_max is selected from the group consisting of not greater than 90%, not greater than 80%, not greater than 70%, not greater than 60%, not greater than 50%, not greater than 30%, not greater than 25%, not greater than 20%, not greater than 15%, not greater than 10%, and not greater than 5% of the T_max exhibited by a non-nanoparticulate composition of the same thiazepine, administered at the same dosage;

(b) the C_max is selected from the group consisting of at least 50%, at least 100%, at least 200%, at least 300%, at least 400%, at least 500%, at least 600%, at least 700%, at least 800%, at least 900%, at least 1000%, at least 1100%, at least 1200%, at least 1300%, at least 1400%, at least 1500%, at least 1600%, at least 1700%, at least 1800%, or at least 1900% greater than the C_max exhibited by a non-nanoparticulate composition of the same thiazepine, administered at the same dosage;

(c) the AUC is selected from the group consisting of at least 25%, at least 50%, at least 75%, at least 100%, at least 125%, at least 150%, at least 175%, at least 200%, at least 225%, at least 250%, at least 275%, at least 300%, at least 350%, at least 400%, at least 450%, at least 500%, at least 550%, at least 600%, at least 750%, at least 700%, at least 750%, at least 800%, at least 850%, at least 900%, at least 950%, at least 1000%, at least 1050%, at least 1100%, at least 1150%, or at least 1200% greater than the AUC exhibited by the non-nanoparticulate formulation of the same thiazepine, administered at the same dosage;

or

(d) any combination thereof.

18. The composition of claim 1 which does not produce significantly different absorption levels when administered under fed as compared to fasting conditions.

19. The composition of claim 18, wherein the difference in absorption of the thiazepine, when administered in the fed versus the fasted state, is selected from the group consisting of less than 100%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, and less than 3%.

20. The composition of claim 1, wherein administration of the composition to a human in a fasted state is bioequivalent to administration of the composition to a subject in a fed state.

21. The composition of claim 20, wherein “

bioequivalency”

is established by;

(a) a 90% Confidence Interval of between 0.80 and 1.25 for both C_max and AUC;

or

(b) a 90% Confidence Interval of between 0.80 and 1.25 for AUC and a 90% Confidence Interval of between 0.70 to 1.43 for C_max.

22. A method of preparing a nanoparticulate anti-hypertensive active agent comprising contacting particles of a thiazepine compound having anti-hypertensive pharmaceutical properties with at least one surface stabilizer for a time and under conditions sufficient to provide a nanoparticulate thiazepine composition having an effective average particle size of less than 2000 nm.

23. The method of claim 22, wherein the thiazepine is temocapril or a salt thereof.

24. The method of claim 23, wherein the salt is the hydrochloride salt.

25. The method of claim 22, wherein the contacting comprises grinding, wet grinding, homogenization, freezing, template emulsion, precipitation, or a combination thereof.

26. The method of claim 22, wherein the effective average particle size of the thiazepine particles is selected from the group consisting of less than 1900 nm, less than 1800 nm, less than 1700 nm, less than 1600 nm, less than 1500 nm, less than 1000 nm, less than 1400 nm, less than 1300 nm, less than 1200 nm, less than 1100 nm, less than 900 nm, less than 800 nm, less than 700 nm, less than 600 nm, less than 500 nm, less than 400 nm, less than 300 nm, less than 250 nm, less than 200 nm, less than 100 nm, less than 75 nm, and less than 50 nm.

27. A method for treating hypertension or a related condition or disease comprising administering to a patient in need a composition comprising:

(a) particles of a thiazepine compound having anti-hypertensive pharmaceutical properties and having an effective average particle size of less than 2000 nm; and

(b) at least one surface stabilizer.

28. The method of claim 27, wherein the thiazepine is temocapril or a salt or derivative thereof.

29. The method of claim 28 wherein the salt is the hydrochloride salt.

30. The method of claim 27, wherein the related disease or condition is selected from the group consisting of ischemic heart disease, stroke, peripheral artery disease, hypertensive heart disease, and renal failure.

31. The method of claim 27, wherein the effective average particle size of the thiazepine particles is selected from the group consisting of less than 1900 nm, less than 1800 nm, less than 1700 nm, less than 1600 nm, less than 1500 nm, less than 1000 nm, less than 1400 nm, less than 1300 nm, less than 1200 nm, less than 1100 nm, less than 900 nm, less than 800 nm, less than 700 nm, less than 600 nm, less than 500 nm, less than 400 nm, less than 300 nm, less than 250 nm, less than 200 nm, less than 100 nm, less than 75 nm, and less than 50 nm.

32. The method of claim 27, wherein the thiazepine particles have improved bioavailability as compare to conventional non-nanoparticulate thiazepine particles.

33. A stable nanoparticulate anti-hypertensive pharmaceutical composition comprising:

(a) particles of a thiazepine compound having anti-hypertensive pharmaceutical properties and having an effective average particle size of about 2000 nm; and

(b) at least one surface stabilizer.

34. A method of preparing a nanoparticulate anti-hypertensive active agent comprising contacting particles of a thiazepine compound having anti-hypertensive pharmaceutical properties with at least one surface stabilizer for a time and under conditions sufficient to provide a nanoparticulate thiazepine composition having an effective average particle size of about 2000 nm.

35. A method for treating hypertension or a related condition or disease comprising administering to a patient in need a composition comprising:

(a) particles of a thiazepine compound having anti-hypertensive pharmaceutical properties and having an effective average particle size of about 2000 nm;

(b) at least one surface stabilizer.