DESC:INTRODUCTION

Aspects of the present invention relates to hot-melt extruded pharmaceutical compositions comprising active agent lacidipine and method of preparation thereof. Aspects of the present invention also provide pharmaceutical formulations comprising hot-melt extruded pharmaceutical compositions of lacidipine along with one or more pharmaceutically acceptable excipients, and method of preparation thereof. Aspects of the present invention further relates to methods of use of pharmaceutical formulations of lacidipine for the treatment of a disease or disorder such as hypertension either alone or in combination with other antihypertensive agents, including ß-adrenoceptor antagonists, diuretics, and ACE-inhibitors.
Lacidipine is a specific and potent calcium antagonist with a predominant selectivity for calcium channels in vascular smooth muscle. Its main action is to dilate peripheral arterioles, reducing peripheral vascular resistance and lowering blood pressure.

“Lacidipine” has a chemical name 3, 5-diethyl 4-{2-[(1E)-3-(tert-butoxy)-3-oxoprop-1-en-1-yl]phenyl}-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate. It has the structural Formula I.

Formula I
Molecular formula of Lacidipine is C26H33NO6 and molecular weight is 455.55.

Lacidipine is a white to pale yellow crystalline powder, practically insoluble in water having a melting point of 174-175°C.

Lacidipine is a dihydropyridine calcium antagonist, which is useful in the treatment of hypertension and is commercially marketed under the brand name MOTENS® by Boehringer Ingelheim available in 2, 4, and 6 mg tablets.

MOTENS® is indicated for the treatment of hypertension either alone or in combination with other antihypertensive agents, including ß-adrenoceptor antagonists, diuretics, and ACE-inhibitors.

MOTENS® tablet contains active agent lacidipine with other inactive ingredients such as Lactose (monohydrate), Lactose (spray-dried), Povidone K30, Magnesium stearate, Titanium Dioxide (E 171), Methylhydroxypropylcellulose

U.S. Patent Nos. 4,801,599 and 5,011,848 describe lacidipine and its related compounds, processes for the preparation of crystalline lacidipine, pharmaceutical compositions containing them, and their use in cardiovascular disorders.

PCT Publication No. WO9508987 describes a process for preparation of solid dispersions and deposits as well as of solid medicinal forms with dihydropyridine type calcium antagonists wherein lacidipine is used as 1, 4-dihydropyridine derivative.

The use of cyclodextrins to enhance stability, aqueous solubility and bioavailability of poorly soluble drugs has been described. U.S. Patent Nos. 5,070,081, 5,942,501, 6,071,964, and 6,828,334 describe methods to enhance stability and/or solubility, and bioavailability, of poorly soluble drugs with cyclodextrins.
U.S. Pat. No. 5,741,519 discloses solid solutions by melt extruding the active substance in a nonionic form together with a salt and a polymer, such as polyvinylpyrrolidone (PVP), inylpyrrolidinone/vinylacetate (PVPVA) copolymer, or a hydroxyalkylcellulose.
Rambali, B., et al., “Itraconazole Formulation Studies of the Melt-Extrusion Process with Mixture Design” Drug Development and Industrial Pharmacy,29(6): pp. 641-652, 2003 discloses solid dispersions of itraconazole by hot-melt extrusion with hydroxypropyl-beta-cyclodextrin and hydroxypropylmethylcellulose for the improvement of aqueous solubility.

Verreck.G. et al., “The Use of Three Different Solid Dispersion Compositions-Melt Extrusion, Film-Coated Beads, and a Glass Thermoplastic System-To Improve the Bioavailability of a Novel Microsomal Triglyceride Transfer Protein Inhibitor”, Journal of Pharmaceutical Sciences, 93(5): p. 1217-1228, 2004, discloses dispersions of a water-insoluble microsomal triglyceride transfer protein inhibitor with improved bioavailability by hot-melt extrusion.

Hulsmann. S et al., “Melt extrusion-an alternative method for enhancing the dissolution rate of 17(ß) - estradiol hemihydrate” European Journal of Pharmaceutics and Biopharmaceutics, 49(3): p. 237-242, discloses solid dispersions of the poorly water soluble drug 17(ß)-estradiol with increased dissolution rate by hot-meltextrusion with polymeric carriers such as polyethylene glycol, PVP, and PVPVA along with various non-polymeric additives.

Forster. A., Hempenstall. J and Rades.T, “Characterization of glass solutions of poorly water soluble drugs produced by melt extrusion with hydrophilic amorphous polymers” Journal of Pharmacy and Pharmacology. 53: pp. 303-315, 2001 discloses amorphous glass solutions with poorly water soluble drugs indomethacin, lacidipine, nifedipine, and tolbutamide in PVP and PVPVA demonstrating improved dissolution compared with the crystalline forms by hot melt extrusion technique. In this article, it is also seen that after storage of the extrudates at 25oC and relative humidity of about 75% only compositions containing indomethacin and polymer in a one to one ratio remained completely amorphous. Compositions of the remaining drugs and compositions with increased indomethacin concentration showed recrystallization upon storage. This recrystallization was shown to significantly decrease the dissolution rate of the active.

The previous reference reveals the inherent instability of amorphous dispersions produced by hot-melt extrusion techniques. Although many articles demonstrate the production of amorphous solid dispersions and the resulting improvement of drug dissolution rate, very few discuss the stability of such preparations on storage. From the work of Foster et al., and an understanding of the thermodynamics of amorphous systems, it can be concluded that recrystallization of amorphous solid dispersion compositions on storage is a common problem. The amorphous state is thermodynamically metastable, and therefore it is expected that amorphous compounds will assume a stable crystalline conformation with time, as well as in response to perturbations such as elevations in temperature and exposure to moisture. In an extruded formulation, amorphous drug particles will agglomerate and crystallize with increasing storage time, elevated temperature, or exposure to moisture, essentially precipitating out of the carrier. This progression towards phase separation during storage results in a time dependant dissolution profile. A change in dissolution rate with time precludes the successful commercialization of a pharmaceutical product.

Although there have been many reports of successful production of solid dispersions by hot-melt extrusion that show improved dissolution rates of poorly water soluble drugs, the absence of numerous marketed products based on this technology is evidence that stability problems remain a major obstacle for successful commercialization of such a pharmaceutical preparation.

The above said problems/limitations of the prior art are overcome by the present lacidipine formulations comprising hot-melt extruded compositions of lacidipine which are stable upon storage and there is no recrystallization of drug during the intended product shelf life and exhibit in vitro dissolution profiles that are comparable to commercially available MOTENS® tablets.

Lacidipine is practically insoluble in water. The poor solubility of lacidipine in aqueous media poses a tremendous challenge to the pharmaceutical formulation scientist in providing for its delivery in adequate concentrations into the systemic circulation. The rate of dissolution of poorly water-soluble drug such as lacidipine is a rate-limiting factor in its absorption by the body. It is generally known that a reduction in the particle sizes of an active ingredient can result in an increase in the dissolution rate of such compounds through an increase in the surface area of the solid phase that comes in contact with the aqueous medium. There is no way to predict the extent to which the dissolution rate of an active will be enhanced through particle size reduction or what is the desirable particle size for achieving desired bioavailability characteristics. Particle size reduction beyond certain values may many times result in material handling and processing issues, such as generation of static charges on new exposed surfaces and agglomeration, thereby resulting in unpredictable variation in solubility, dissolution, and hence bioavailability.

The inventors of the present invention have found that formulations containing hot-melt extruded composition of lacidipine exhibit improved in-vitro dissolution profiles over existing conventional marketed dosage forms of lacidipine. Further, the formulations of the present invention do not require micronization, or substantial particle size reduction of lacidipine by mechanical means. The development, on a commercial scale, of a stable pharmaceutical formulation comprising lacidipine poses a challenge, which heretofore, has yet been unmet. The present invention alleviates the limitations of the prior art.

SUMMARY
Aspects of the present invention provide hot-melt extruded pharmaceutical compositions comprising active agent lacidipine or its salts.

Aspects of the present invention provide hot-melt extruded pharmaceutical compositions comprising lacidipine or its salts, one or more polymers and optionally one or more pharmaceutically acceptable excipients.

Aspects of the present invention provide hot-melt extruded pharmaceutical compositions comprising lacidipine or its salts, one or more polymers, one or more solubilizers and optionally one or more pharmaceutically acceptable excipients.

In aspects, the present invention provides pharmaceutical formulations containing hot-melt extruded pharmaceutical compositions of lacidipine or its salts in the form of tablets, capsules, granules, pellets, beads, particles, mini-tablets, or orally disintegrating tablets etc.

In aspects, the present invention provides pharmaceutical formulations in the form of tablet and/or capsule containing hot-melt extruded pharmaceutical compositions of lacidipine or its salts.
An aspect of the present invention provides pharmaceutical formulations comprising hot-melt extruded pharmaceutical compositions of lacidipine or its salts, wherein the lacidipine or its salt are stable during the preparation and also during the shelf-life.

An aspect of the present invention provides pharmaceutical formulations comprising hot-melt extruded pharmaceutical compositions of lacidipine or its salts, wherein lacidipine or its salt are stable during the preparation and also during the shelf-life.

An aspect of the present invention relates to pharmaceutical formulations comprising hot-melt extruded pharmaceutical compositions of lacidipine or its salts, wherein the percentage of lacidipine or its salt released is not less than about 70% within about 60 minutes when subjected to an in vitro dissolution study.

An aspect of the present invention relates to pharmaceutical formulations comprising hot-melt extruded pharmaceutical compositions of lacidipine or its salts as active agent, wherein the said active agent is present in an amount of about 0.5 mg to about 25 mg, or about 1 mg to about 10 mg.

An aspect of the present invention relates to pharmaceutical formulations comprising lacidipine melt extrudates wherein weight ratios of lacidipine to the polymer is in the range of about 0.001:1 to 0.2:1.
An aspect of the present invention relates to pharmaceutical formulations comprising hot-melt extruded pharmaceutical compositions of lacidipine or its salts, wherein methods for preparing the said dosage formulations include one or more of the steps of mixing, hot-melt extrusion, milling, blending, lubrication, compression and coating.

An aspect of the present invention relates to pharmaceutical formulations comprising hot-melt extruded pharmaceutical compositions of lacidipine or its salts, wherein said dosage form is packaged into a blister, HDPE container or any other suitable packaging optionally together with a desiccant and/or oxygen absorbent.

Aspects of the present invention relate to processes for preparation of hot-melt extruded pharmaceutical compositions of lacidipine or its salts.

Aspects of the present invention relate to processes for preparation of pharmaceutical formulations comprising hot-melt extruded pharmaceutical compositions of lacidipine or its salts and one or more
pharmaceutically acceptable excipients.

Aspects of the present invention relates to methods of use of pharmaceutical formulations of hot-melt extruded pharmaceutical compositions of lacidipine or its salts for the treatment of a disease or disorder such as hypertension either alone or in combination with other antihypertensive agents, including ß-adrenoceptor antagonists, diuretics, and ACE-inhibitors.

The formulations of the present invention are stable and provide the desired therapeutic concentration of the active agent for the intended duration.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure.1; XRPD Initial chromatogram of lacidipine A) API, B) Formulation example 1 A and C) Placebo

Figure.2; XRPD chromatogram of A) lacidipine API (40oC, 75%RH -3 Months), B) Formulation example 1 A (40oC, 75%RH- 3 Months) and C) Placebo (40oC, 75%RH-3 Months)

Figure 3: Comparative graphical presentation for in-vitro drug release in 0.1 % Tween-20 at 50 RPM.

DETAILED DESCRIPTION

Aspects of the present invention relates to hot-melt extruded pharmaceutical compositions comprising active agent lacidipine and method of preparation thereof.

Aspects of the present invention also provide pharmaceutical formulations comprising hot-melt extruded pharmaceutical compositions of lacidipine along with one or more pharmaceutically acceptable excipients, and method of preparation thereof.

Unless mentioned otherwise, the active agent lacidipine is intended to include lacidipine or any of its pharmaceutically acceptable salts, solvates, hydrates, enantiomers, or mixtures thereof, without limitation.
“Lacidipine composition” or “ hot melt extruded lacidipine composition” or “lacidipine melt extrudates” or “melt extrudate” or “extrudates” means compositions wherein lacidipine, together with one or more polymers and optionally at least one solubilizer is present as a melt extruded composition.

The term “formulation” as used herein refers to pharmaceutical dosage forms comprising hot-melt extruded pharmaceutical compositions of lacidipine compositions and one or more pharmaceutically acceptable excipients as desired for the effective delivery of lacidipine to a subject in need thereof.
In embodiments, the present invention provides stable melt extruded lacidipine composition, wherein the said composition comprises lacidipine and a polymer such that the lacidipine is present in an amount of less than about 20% w/w of the composition, or less than about 10% w/w of the composition, or less than about 5% w/w of the composition.

In embodiments, the present invention provides stable formulation comprising hot-melt extruded pharmaceutical compositions of lacidipine, wherein the lacidipine is present in an amount of less than about 10% w/w of the formulation, or less than about 5% w/w of the formulation, or less than about 2.5% w/w of the formulation.

In embodiments, the present invention provides stable formulation comprising hot-melt extruded pharmaceutical compositions of lacidipine, wherein the said formulation possesses appreciable storage stability at accelerated conditions (i.e., a temperature of about 40°C and about 75% RH) for a period of at least 6 months.

In embodiments, the invention relates to pharmaceutical compositions and formulations of lacidipine having improved solubility characteristics that exhibit improved dissolution profiles of lacidipine.

For a poorly water soluble drug such as lacidipine, one effective formulating approach is preparation of glass solution with the drug and hydrophilic excipient to increase solubility. In a glass solution, the drug is molecularly dissolved and has a lower thermodynamic barrier for dissolution. Hot-melt extrusion processes yield what are called glass solutions, enabling formulation of poorly soluble drugs with otherwise limited bioavailability. Hot-melt extrusion technology shows numerous benefits over other methods, including shorter processing times, few processing steps, the ability for continuous operation, environmental advantages due to the elimination of solvents, and efficient delivery of drugs to patients through formation of solid dispersions and improved bioavailability.

Lacidipine is a highly insoluble drug and the dissolution of lacidipine in 500 ml of dissolution media of Purified Water containing 0.1% polysorbate 20 was performed using USP Apparatus-II (Paddles) at 50 RPM paddle speed. It was observed that the release of lacidipine is only about 12% after 120 minutes.
Lacidipine has a very high melting point of about 178°C. It is thermally stable up to 180°C and degrades with melting beyond 200°C. These characteristics of Lacidipine confirm the feasibility of utilizing melt extrusion technology for extrusion of Lacidipine-containing mixtures.

Aspects of the present invention relate to pharmaceutical formulations comprising hot melt extruded Lacidipine compositions and other pharmaceutically acceptable excipients, and method of preparation thereof.

In embodiments, the present invention relates to pharmaceutical formulations comprising melt extruded lacidipine compositions and other pharmaceutically acceptable excipients, wherein the lacidipine is present in substantially particulate form.

Aspects of the present invention provide hot-melt extruded pharmaceutical compositions comprising lacidipine, one or more polymers, and optionally one or more pharmaceutically acceptable excipients.
In embodiments, a polymer useful to prepare melt extrudates should be capable of having a strong interaction with the drug lacidipine, leading to complete miscibility of drug in the polymer which is usually evident from single Tg of the system.

In embodiments, the polymer is selected from a group comprising an ionic or non-ionic polymer, such as a polymethylmethacrylate, polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone¬polyvinylalcohol, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, or methylcellulose acetate phthalate or mixtures thereof. Compositions can also contain polymeric surfactants such as poloxamers.
In embodiments, the present invention relates to pharmaceutical compositions comprising lacidipine melt extrudates wherein weight ratios of lacidipine to the polymer is in the range of about 0.001:1 to 0.2:1.

In embodiments, the polymer used in the preparation of lacidipine melt extrudates is copovidone.
In aspects, the pharmaceutical compositions of lacidipine in the form of hot melt extrudate comprise a polymer and a solubilizer. In embodiments, the weight ratio of lacidipine to solubilizer is in the range of about 10:0.1 to about 0.1:10.

In embodiments, the present invention relate to pharmaceutical formulations comprising melt extruded lacidipine compositions and one or more other pharmaceutically acceptable excipients, wherein the lacidipine compositions are in the form of physically stable solid dispersions containing lacidipine in a substantially particulate form.

In embodiments, the pharmaceutical compositions comprising lacidipine melt extrudates possess improved solubility as compared to compositions of lacidipine prepared using another process.
In embodiments, pharmaceutical compositions and formulations thereof comprising lacidipine melt extrudates of the present invention exhibit in vitro dissolution profiles that are comparable to commercially available MOTENS® tablets.

In embodiments, pharmaceutical formulations comprising lacidipine melt extrudate compositions possess excellent storage stability for commercially relevant time periods.

Aspects of the present invention provide pharmaceutical formulations comprising lacidipine or its salt, which exhibit appreciable chemical stability and physical/polymorphic stability during the preparation and also during the shelf-life of the formulations.

Embodiments of the present invention provide pharmaceutical formulations in the form of a solid oral dosage form comprising lacidipine or its salt, and one or more pharmaceutically acceptable excipients, wherein the solid dosage form is coated.

In an embodiment, the pharmaceutical formulation comprising lacidipine remains stable when stored at accelerated storage conditions (i.e., at about 40°C and 75% RH), for at least 6 months. For example, the total Lacidipine-related impurities formed in the stable compositions upon such storage do not exceed about 3.5%.

In aspects, the present invention relates to pharmaceutical formulations in a solid oral dosage form such as capsule comprising melt extruded lacidipine compositions. In embodiments, the melt extruded lacidipine compositions are in the form of powders, granules, beads, pellets, mini-tablets, and the like.

In an embodiment, the present invention relates to pharmaceutical formulations comprising melt extruded lacidipine compositions in the form of a tablet.

In embodiments, the present invention provides process of preparing pharmaceutical compositions and formulations thereof comprising lacidipine. In embodiments, the present invention provides process of preparing tablet formulation of lacidipine wherein the process comprises one or more of the steps of mixing, hot-melt extrusion, milling, blending, lubrication, compression and coating.

The “Hot-melt Extrusion” is the process of embedding drug in a polymeric carrier. It is a process of converting a raw material into a product of uniform shape and density by forcing it through a die under controlled conditions. It can be simply defined as the process of forming a new material (the extrudate) by forcing it through an orifice or die under controlled conditions, such as temperature, mixing, feed-rate and pressure using a Hot Melt Extruder.

In hot-melt extruded drug delivery systems, the active compound is embedded in a carrier formulation comprised of one or more meltable substances and other functional excipients. The meltable substances may be polymeric materials or low melting point waxes. The selection of polymer for hot-melt extrusion process mainly depends on drug–polymer miscibility, polymer stability and function of final dosage form. According to aspects of the present invention, polymers which have an appreciable miscibility with lacidipine are employed. However, low melting point waxes or their combination with polymer may also be employed in the preparation of hot melt extrudates of lacidipine.

In embodiments of the present invention, the complete extrusion process comprises of three steps: a) a conveying and kneading system for material transport and mixing, b) a die system for forming the extrudates and c) downstream auxiliary equipment (cooling, pelletizing and collecting). In embodiments, the hot-melt extruder comprises of barrels enclosing single, two or multi-screws.

In embodiments, the extrudates can be in the form of beads, granulates, tube, strand or cylinder, and this can be further processed into any desired shape.

In embodiments, the hot-melt extruder comprises of gravimetric feeder or volumetric feeder, preferably gravimetric feeder.

In aspects, the present invention relates to process for preparing pharmaceutical compositions comprising lacidipine, wherein the said process comprises the following steps:

(i) Combining lacidipine and a polymer and heating the mixture of drug and polymer above the glass transition temperature of the polymer,

(ii) Extruding the melted mixture of (i) to obtain extrudates, and

(iii) Milling the extrudates to produce desired particle size.

In aspects, the present invention relates to process for preparing pharmaceutical formulations comprising lacidipine, wherein the said process comprises the following steps:

(i) Combining lacidipine and a polymer and heating the mixture of drug and polymer above the glass transition temperature of the polymer,

(ii) Extruding the melted mixture of (i) to obtain extrudates,

(iii) Milling the extrudates to produce desired particle size,

(iv) Blending milled extrudates with one or more other excipients, and

(v) Making the blend into a suitable dosage form such as filling into a capsule or compressing into a tablet.

According to embodiments of the invention, particle size distributions of lacidipine which is subjected to hot-melt extrusion have D10 less than about 20 µm, D50 less than about 100 µm, and D90 less than about 250 µm.

In embodiments, pharmaceutical formulations comprising lacidipine melt extrudates were subjected to storage stability testing at 25°C and 60% RH, and 40°C and 75% RH, for a commercially relevant time period and analyzed for drug-related impurities. The total impurities were found to be less than about 2.5% w/w of the label lacidipine content at the end of three months of storage at both 25°C and 60% RH, and 40°C and 75% RH storage conditions.

In embodiments, pharmaceutical compositions comprising lacidipine melt extrudates are characterized for solubility, bulk density, tapped density, Hausner ratio, moisture content, Carr index, angle of repose, blend particle sizes, and other parameters useful in the characterization of pharmaceutical compositions.
The different physicochemical properties of the active agent as well as of excipients are to be considered, as these properties affect processing and formulation aspects. Various important physicochemical properties include, but are not limited to, particle size, density (bulk density and tapped density), compressibility index, Hausner’s ratio, angle of repose, etc. Particle size of active pharmaceutical ingredient can affect the solid dosage form in numerous ways. For example, content uniformity (CU) of pharmaceutical dosage units can be affected by particle size and size distributions. Also, particle sizes can play an important role in the dissolution of active agent from the final dosage forms, because of their solubility. Hence, these physicochemical properties not only affect the processes of preparing the pharmaceutical compositions but also affect the performance of the pharmaceutical product, both in vitro and in vivo.

In embodiments, pharmaceutical compositions comprising Lacidipine melt extrudates have bulk density and tapped density less than about 0.7-1.2 g/cc and Carr’s index values less than about 30%, or less than about 20%, thus representing good flow properties.

In embodiments, pharmaceutical compositions comprising lacidipine melt extrudates have moisture contents less than about 8%, or less than about 5%, by weight.

In embodiments, pharmaceutical formulations comprising lacidipine melt extrudates have blend
particle sizes such that more than about 50% of the particles are smaller than 420µm.

In embodiments, pharmaceutical formulations of the present invention include any desired number of additional excipients, such as one or more of surfactants, emulsifiers, pH modulators, fillers, binders, diluents, disintegrants, glidants, lubricants, flavors, colorants, and the like.

In embodiments, lacidipine compositions of the present invention comprise one or more miscible polymers that are ionic or non-ionic polymers, or mixtures thereof.

Non-limiting examples of ionic and nonionic polymers useful in the present invention are polymethylmethacrylates, polyvinylpyrrolidones, hydroxyethyl celluloses, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, polyvinylpyrrolidone-polyvinylalcohols, hydroxypropyl methylcellulose acetate succinates, hydroxypropyl methylcellulose phthalates, polyvinyl acetate phthalates, cellulose acetate phthalates, hydroxypropyl cellulose acetate phthalates, and methylcellulose acetate phthalates, and mixtures thereof. Compositions can also contain polymeric surfactants such as poloxamers.

In embodiments, the compositions contain polymers such as polyvinyl pyrrolidones.

In embodiments, the polymers present in the composition are in the range of about 1-90% or 30-90% by weight of the total composition.

In embodiments, the compositions contain Kollidon VA64 as polymer for hot-melt extrusion. Lacidipine-polymer blends were found to be chemically stable and there was no significant increase in impurities during and after the extrusion process. In an aspect, the melt extruded composition contained less than 1.5% of total impurities by weight of labeled amount of lacidipine.

In embodiments, pharmaceutical compositions of the present invention comprise at least one solubilizer, such as a poloxamer (e.g., Lutrol® F 68), polyethoxylated castor oil (e.g., Cremophor® RH 40), diacetylated monoglyceride, dibutyl sebacate, D-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS) diethyl phthalate, glycerin, polyethylene glycol, propylene glycol, or triacetin, triethyl citrate, or mixtures thereof.

In embodiments the preferred solubilizers for the present composition are poloxamer (e.g., Lutrol® F 68) and D-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS).

In embodiments, the lacidipine formulations optionally contain disintegrants.

Examples of suitable disintegrants include natural starches such as maize starch and potato starch; directly compressible starches such as starch 1500; modified starches such as carboxymethyl starch and sodium starch glycolate; starch derivatives such as amylase; various grades of crospovidone; croscarmellose sodium; alginic acid and sodium alginate; microcrystalline celluloses; crosslinked polymers; crosslinked starches; cationic and anionic ion exchange resins; and the like, and mixtures thereof.

In embodiments, the disintegrants present in the composition are preferably in the range of 0-20%, or 0-10% by weight of the total composition.

Solubilizers improve the wettability of the active agent. Various useful solubilizers include, but are not limited to surfactants such as, sodium lauryl sulfate, cetrimide, polysorbates such as polysorbate 80, poloxamers such as poloxamer 188 and poloxamer 407, sodium carboxymethylcelluloses, hydrogenated oils, polyoxyethylene glycols, polyoxypropylene glycols, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyglycolized glycerides, such as are available commercially as GELUCIRE® 40/14, GELUCIRE® 42/12, and GELUCIRE® 50/13, vitamin E TGPS, TWEEN® surfactants, SPAN® surfactants, and mixtures thereof.

In embodiments, the solubilizers present in the composition are about 40%, or about 20%, or about 10% by weight of the total composition.

Emulsifying agents can include any of a wide variety of cationic, anionic, zwitterionic, and amphoteric surfactants known in the art.

Various useful diluents include, but are not limited to calcium sulfate, cellulose acetate, dextrates, dextrin, dextrose, fructose, kaolin, lactitol, maltitol, maltodextrin, maltose, polymethacrylates, sodium chloride, sucrose and talc, starches, lactose, mannitol, cellulose derivatives and the like, and mixtures thereof. Different grades of lactose include but are not limited to lactose monohydrate, lactose DT (direct tableting), lactose anhydrous, Flowlac™, Pharmatose™ and others. Different grades of starches included but are not limited to maize starch, potato starch, rice starch, wheat starch, pregelatinized starch and Starch 1500, Starch 1500 LM grade (low moisture content grade), fully pregelatinized starch and others. Different cellulose compounds that can be used include crystalline cellulose and powdered cellulose, and cellulose acetate. Examples of crystalline cellulose products include but are not limited to CEOLUS™ KG801, Avicel™ PH101, PH102, PH301, PH302 and PH-F20, microcrystalline cellulose 114, silicified microcrystalline cellulose and microcrystalline cellulose 112. Other useful diluents include but are not limited to carmellose, sugar alcohols such as mannitol, sorbitol and xylitol, calcium carbonate, magnesium carbonate, sodium carbonate, sodium bicarbonate, light magnesium oxide, heavy magnesium oxide, sodium hydrogen phosphate, calcium sulfate, disodium hydrogen phosphate basic calcium phosphate, and tribasic calcium phosphate, or mixtures thereof.

In embodiments the diluents present in the composition are in the range of 1-90%, or 30-90% by weight of the total composition.

In embodiments, various useful binders include, but are not limited to, carboxymethyl cellulose, hydroxyethylcellulose, dextrin, gelatin, maltodextrin, polyethylene oxide, sodium alginate, hydroxypropylcellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone or povidone (PVP-K25, PVP-K29, PVP-K30, PVP- K90D), copovidones, powdered acacia, gelatin, guar gum, carbomers (e.g., Carbopol™ products), methylcelluloses, polymethacrylates, starches, and mixtures thereof.
In embodiments the binders present in the composition are in the range of 2-25%, or 2.5-20%, or 5-15% by weight of the total composition.

In embodiments, the composition optionally contains various glidants or anti-adherents which include, but are not limited to, talc, silica derivatives, colloidal silicon dioxide, and the like, or mixtures thereof.

In embodiments the glidants present in the composition are preferably in the range of 0-5%, or 1-3% by weight of the total composition.

Various lubricants that can be used include, but are not limited to, stearic acid and stearic acid derivatives such as magnesium stearate, calcium stearate, zinc stearate, sucrose esters of fatty acids, polyethylene glycols, talc, sodium stearyl fumarate, sodium laurylsulphate, glyceryl behenate, glyceryl monostearates, palmitic acid, talc, carnauba wax, calcium soaps, zinc stearate, polyoxyethylene monostearates, calcium silicate, silicon dioxide, or macrogols, or mixtures thereof.

In embodiments, the lubricants present in the composition are in the range of 0-10%, or 0.5-3% by weight of the total composition.

Coloring agents optionally contained in the compositions of the present invention can include but not limited to Iron oxide, Lake of sunset yellow, Lake of Quinoline yellow, Lake of erythrosine, Titanium dioxide and the like, or mixtures thereof.

The pharmaceutical hot melt extruded lacidipine compositions of the present invention may be in the form of solid dosage forms or liquid dosage form such as suspensions. The formulations thereof are prepared using any process operations, such as one or more of wet granulation, dry granulation, direct compression, compaction, spheronization, and any other technique known to the art.

The present invention provides pharmaceutical compositions which are stable and provide the desired therapeutic concentration of the active agent for the intended duration.
In an embodiment, the present invention provides pharmaceutical compositions comprising lacidipine in crystalline form, or amorphous form, or mixtures thereof.

As used herein, “pharmaceutically acceptable salts” or “its salts” includes metal or amine salts, but is not limited to, sodium, potassium, lithium, calcium, magnesium, aluminum, iron, or zinc salts. Such salts may be derived from bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide, aluminum hydroxide, ferrous or ferric hydroxide, etc. The term "pharmaceutically acceptable amine salt" includes, but is not limited to, salts formed by reaction with ammonium hydroxide or organic amines such as for example methylglucamine, choline, arginine, 1 -deoxy-2-(methylamino)-D-glucitol, and the like.

The amounts of an active ingredient in the pharmaceutical compositions of the present invention will be a therapeutically effective amount. In embodiments, lacidipine present in the compositions of the invention ranges from about 0.05% to about 70% or from about 0.5 % to about 60% or from about 1% to about 50%, by weight, based on the total weight of the pharmaceutical compositions.
As used herein, the active agent lacidipine include the compounds and prodrugs thereof, active metabolites of the compounds and the prodrugs thereof, their salts, esters, polymorphic forms, solvates, hydrates, and single enantiomers thereof.

The term "excipient" or "pharmaceutically acceptable excipient" means a component of a pharmaceutical product that is not an active ingredient, such as a filler, diluent, carrier, etc. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and neither biologically nor otherwise undesirable, and are acceptable for veterinary use as well as human pharmaceutical use. An "excipient" or a “pharmaceutically acceptable excipient" as used in the specification includes one and more than one such excipient.

The term "about" refers to quantitative terms, plus or minus 20%.

The term “stability” as used herein includes both chemical stability and physical/polymorphic stability. The term ‘stability’ is defined as the capacity of a drug substance or drug product to remain within the established specifications to maintain its identity, strength, quality and purity throughout the retest or expiration dating period. The term ‘chemical stability’ means the tendency of drug to resist change or decomposition due to internal reaction, or due to the effects of oxygen, heat, light, pressure, and the like. The term “physical/polymorphic stability” refers to maintaining the physical/polymorphic form of the active agents, such as crystalline, amorphous, or mixtures thereof, and “chemical stability” refers to maintaining acceptable concentrations of drug-related impurities.

The term ‘shelf life’ is the time that finished products can be stored after manufacturing, during which the defined quality of a specified proportion of the product remains acceptable under expected (or specified) conditions of distribution, storage, and display.

The selection of appropriate particles sizes of the active agents, as well as of excipients, is within the scope of the invention. D10, D50, and D90 values are useful ways for indicating a particle size distribution. D90 is the size value where at least 90 volume percent of the particles have sizes smaller than the value.

In embodiments, compositions of the present invention are in the form of film-coated tablets. Useful coating compositions comprise conventional film-coating materials such as Opadry® products (manufactured by Colorcon, such as Opadry white 03A58901, Opadry white OY 58900, Opadry white AMB OY B 28920, Opadry AMB OY-B-29000 & other hydrophilic or hydrophobic substances, and mixtures thereof. Useful additives for coating include, but are not limited to, plasticizers, antiadherents, opacifiers, solvents, and optionally colorants, lubricants, pigments, antifoam agents, and polishing agents, or mixtures thereof.

In an aspect, the film coating contains the following components: polymer(s), plasticizer(s), colourant(s)/opacifier(s), and vehicle(s). In the film coating suspension minor quantities of flavours, surfactants and waxes can be used. The majority of the polymers used in film coating are preferably either cellulose derivatives, such as cellulose ethers, or acrylic polymers and copolymers. High molecular weight polyethylene glycols, polyvinyl pyrrolidone, polyvinyl alcohol and waxy materials can also be used.
Plasticizers include materials that can be categorized into three groups: polyols (such as glycerol, propylene glycol, macrogols), organic esters (such as pthalate esters, dibutyl sebacetate, citrate esters, triacetin), oils/glycerides (such as castor oil, acetylated monoglycerides, fractionated coconut oil).
Pigments, opacifiers such as titanium dioxide, talc, and other additives may also be included in a coating composition. The quantities of the coating may vary from about 0.1-20%, or about 0.5-5%, by weight of the total weight of a core composition. In embodiments, a coating is applied either directly onto the cores or onto sub-coated cores, using conventional coating techniques such as, for instance, pan coating or fluidized bed coating methods.

Antiadherents are frequently used in film coating processes to avoid sticking effects during film formation and drying. An example of a useful antiadhesive for this purpose is talc. The antiadherent is frequently present in a film coating in amounts of about 0.5% (w/w) to 15% (w/w), based upon the total weight of the coating.

Suitable colorants/opacifiers can be selected from several groups such as organic dyes and lacquers, inorganic colors, and natural colors.

Film coating dispersions can be prepared using various vehicles, such as water, alcohols, ketones, esters, chlorinated hydrocarbons, and any mixtures thereof.

In embodiments, tablet compositions of the present invention may comprise a sub-coating, onto which a film coating is provided.

In embodiments, compositions may be prepared by extrusion and spheronization, or using a melt granulation technique. Compositions may be presented as uncoated, film coated, sugar coated, compression coated, or powder coated forms.

The descriptions of excipients are illustrative and are not intended to be exhaustive or limiting. Those skilled in the art will be aware of many other substances that are useful in the practice of the invention, and the use of such substances is specifically included in this invention.

In embodiments, the compositions of the present invention are in the form of powders, beads, granules, pellets, spheroids, extrudates, mini-tablets, and the like.

In embodiments, compositions of the present invention are in the form of powders, beads, granules, pellets, spheroids, extrudates, mini-tablets etc. filled into capsules.

In embodiments, compositions of the present invention are in the form of multiple particles such as granules or pellets that are further made into suitable dosage forms, like capsules, tablets and the like.

In embodiments, tablets/minitablets can be formed in any shapes and sizes, such as round, elongated, capsule-shaped, etc. In embodiments, tablets can be embossed or debossed. To form tablets, compression punches can be coated or uncoated punches and plain, concave, or convex in shape.

In embodiments, compositions of the present invention are in the form of multiple particles such as granules or pellets that are further made into suitable dosage forms, wherein the particles have Carr’s indices in the range of about 1-40%. This indicates superior handling capabilities during processing into pharmaceutical dosage forms. Flowability of materials can be measured and represented using the Carr’s Index.

In embodiments, tablets have hardness values such as 5-50 kiloponds (KP), or 5-30 KP. In embodiments, tablets have friability less than 5%, or less than 2%, or less than 1%. In embodiments, tablet compositions have ‘loss-on-drying’ (LOD) less than about 10%, or less than about 5%, after manufacturing and during their shelf-life.

In embodiments, humidity conditions for the processing area are controlled, so that the processes are carried out below about 40% relative humidity (RH) at about 25°C. Low moisture content is useful to impart improved drug polymorphic stability to the pharmaceutical formulation. Excipients having moisture content less than about 10%, or less than about 5%, are also useful to aid in preventing drug polymorphic conversions.

In embodiments, pharmaceutical formulations are prepared using any of direct compression, dry granulation, or wet granulation method, fluidized bed granulation, hot-melt granulation or combination of such methods.

After granulation, drying can be carried out using an oven dryer, a fluidized bed dryer, and the like, crushing, and sieving can be carried out to obtain granules or fine granules for use.

In embodiments, the pharmaceutical formulations of the present invention are intended for oral administration to a subject in need thereof.

In aspects, the invention provides methods of prophylaxis, amelioration, or treating a disease(s) and/or a disorder(s), by administering a therapeutically effective amount of the formulation to subjects in need thereof.

In an aspect, the present invention provides methods of treatment using pharmaceutical formulations comprising lacidipine.

In an aspect, the present invention provides pharmaceutical formulations comprising lacidipine for the treatment of hypertension either alone or in combination with other antihypertensive agents, including ß-adrenoceptor antagonists, diuretics, and ACE-inhibitors.

The following examples further describe certain specific aspects and embodiments of the invention.

These examples are provided solely for the purpose of illustration, and should not be construed as limiting the scope of the disclosure in any manner.

Example 1: Lacidipine formulations

A. Composition of Tablets
Ingredients (mg/tab) Example-1A Example-1B
Extrudates
Lacidipine 4 2
Kolidone VA 64 72 36
D-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS) 4 2
Extragranular Excipients
Lactose anhydrous
(DCL 21) 178.5 89.25
Povidone (PVP K90) 25 12.5
Povidone (PVP K30) 15 7.5
Magnesium stearate 1.5 0.75
Coating
Opadry white (03A58901) 8 5
Purified water* q.s. q.s.
Total weight (mg) 308 155
*lost during processing

B. Manufacturing Process
1. Accurately weighed quantity of Kollidon VA 64 was sifted and granulated in RMG using melted (40oC-50oC) Speziol TPGS.
2. The granulated blend was sifted.
3. Drug was sifted and blended in double cone blender.
4. The blend was extruded on Hot melt extruder (16M Thermo Scientific)
5. The extrudates were milled using Quadra co-mill and sifted.
6. Other excipients were sifted and mixed with extrudates in blender.
7. The blend was lubricated with magnesium stearate.
8. The final lubricated blend was compressed on Cadmac compression machine
9. The compressed tablets were coated using Opadry white aqueous solution.
Hot-melt Extrusion Process Parameters

A suitable twin screw extruder is the ThermoScientific 16 mm pharmaceutical twin screw extruder. At the end of the twin screw extruder a die is located with a bore of approximately 3 mm. The extruder is equipped with a gravimetric feeder. The twin screw extruder is equipped with individual zones, which can be independently adjusted to different parameters. Starting from the hopper to the die the zones are respectively heated to the following temperatures: 35°C, 95°C, 120°C, 170°C. The screw speed is set at 300 rpm and the feed rate is approximately 1 kg/hr.

The particle size analysis of the extrudates had been performed and the distribution is given in Table-1.
Table- 1: Particle size distribution of extrudates Example-1A
Sieve Size % Retained
#20 0
#35 29
#50 34
#80 16
#100 6
Base plate 15

It was observed that about 29% of extrudates are in the range of about 500-841 µm, 34% of extrudates are in the range of about 297-500 µm, 16% of extrudates are in the range of about 177-297 µm, 6% of extrudates are in the range of about 149-177 µm, and 15% of extrudates are below about 149 µm.
The pharmaceutical compositions comprising lacidipine melt extrudates were subjected to dissolution study. The study showed that more than about 50% of the drug is dissolved within 60 minutes after immersion into ¬¬¬¬¬¬500 ml 0.1% Tween-20 in purified water wherein the dissolution is conducted using USP type II (paddle type) apparatus with 50 RPM stirring at 37±0.5?C. The data is shown in Table-2.

Table 2: In- vitro dissolution of coated tablets

The study also indicates that the dissolution profile of formulations of Example-1A and Example-1B are comparable with the innovator.

The formulation of Example-1A was subjected to a stability study by exposing the packed formulation in Alu-Alu blister pack for 6 months at 40°C/ 75%RH. The study samples were subjected to dissolution study in ¬¬¬¬¬¬500 ml 0.1% Tween-20 in purified water as dissolution media kept at 37±0.5?C using USP type II (paddle type) apparatus with 50 RPM stirring. The data is provided in Table-3.

Table 3: Dissolution profile of initial and 6 months Stability sample of Lacidipine Tablets

The study indicated that there was no substantial change in the drug release profile for the formulation even after the stability study.

Example-2: Lacidipine Formulations:

Ingredients Example-2 (Quantity per tablet (mg))
2 A 2 B 2 C 2 D
Drug Loading (%) 10 15 20 10
Lacidipine 4 4 4 4
Kollidone VA64 36 22.67 16 32
Lutrol F-68 - - - 4
Extra granular Ingredients
Milled extrudates * 40 26.67 20 40
Lactose anhydrous (DCL-21) 253.5 266.83 273.5 253.5
Magnesium Stearate 1.5 1.5 1.5 1.5
Total weight 295 295 295 295
*Based on 100 % drug assay.
Manufacturing Process:

1. Accurately weighed quantity of Kollidon VA 64 and drug was sifted and blended in double cone blender.
2. The blend was extruded on hot-melt extruder (16M Thermo Scientific).
3. The extrudates were milled using Quadra co-mill and sifted.
4. Other excipients were sifted and mixed with extrudates in blender.
5. The blend was lubricated with magnesium stearate.
6. The final lubricated blend was compressed on Cadmac compression machine.
7. The compressed tablets were coated on Neocota coating equipment using Opadry white 10% aqueous solution.

The data is provided in Table-4.
Table 4: Dissolution profiles

The batch 2D with solubilizer (Lutrol F-68) shows about 50% more drug release than with the batch 2A without solubilizer.

It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by the preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and such modifications and variations are considered to be falling within the scope of the invention.

It is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of “including,” “comprising”, or “having” and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.

CLAIMS:WE CLAIM

1. A stable pharmaceutical formulation comprising hot-melt extruded lacidipine composition, wherein the lacidipine is present in an amount of less than about 20% w/w of the composition.

2. The formulation of claim 1, wherein the hot-melt extruded lacidipine composition comprises one or more polymers, one or more solubilizers and optionally one or more pharmaceutically acceptable excipients.

3. The formulation of claim 2, wherein the weight ratios of lacidipine to polymer in the composition is from 0.001:1 to 0.2:1

4. The formulation of claim 2, wherein the polymer is selected from one or more of polyvinylpyrrolidone¬vinyl acetate copolymer, polymethylmethacrylate, polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethylcellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate,methylcellulose acetate phthalate or any mixtures thereof.

5. The formulation of claim 2, wherein the solubilizer is selected from one or more of poloxamer, D-alpha tocopheryl polyethylene glycol 1000 succinate. sodium lauryl sulfate, cetrimide, polysorbates, sodium carboxymethylcelluloses, hydrogenated oils, polyoxyethylene glycols, polyoxypropylene glycols, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyglycolized glycerides or any mixtures thereof.

6. The formulation of claim 3, comprising polyvinylpyrrolidonevinylacetate copolymer, D-alpha tocopheryl polyethylene glycol 1000 succinate and optionally one or more pharmaceutically acceptable excipients.

7. A process for preparing the formulation of claim 2, the process comprising the steps of: (i) preparing lacidipine melt extrudates comprising lacidipine, a polymer, a solubilizer and optionally one or more pharmaceutically acceptable excipients; and (ii) milling the extrudates.

8. The process of claim 7, wherein the process further comprises the steps of blending of the milled lacidipine melt extrudates with one or more pharmaceutically acceptable excipients and making the blend into a capsule or a tablet.

9. The formulation of claim 1, wherein the formulation has an in vitro dissolution profile, when measured in a type II Paddle dissolution apparatus in purified water with 0.1% Tween-20 at about 50 rpm, of not less than about 70% lacidipine release within about 60 minutes.

10. The formulation of claim 1, which is stable for a period of atleast 6 months on exposure to 40?C and 75% RH.