FORM 2
THE PATENTS ACT 1970 (Act 39 of 1970)
PROVISIONAL SPECIFICATION
(SECTION 10)
"PHARMACEUTICAL COMPOSITION COMPRISING LERCANIDIPINE OR SALTS THEREOF"
Glenmark Pharmaceuticals Limited An Indian Company, registered under the Indian company's Act 1957 and having its
registered office at Glenmark Pharmaceuticals Limited
Glenmark House
HDO-Corporate Building, Wing -A
B. D. Sawant Marg
Chakala, Off Western Express Highway
Andheri [East], Mumbai 400099
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION
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"PHARMACEUTICAL COMPOSITION COMPRISING LERCANIDIPINE OR SALTS THEREOF."
BACKGROUND OF THE INVENTION
Technical Field
The present invention relates to an immediate release pharmaceutical composition that achieves rapid release of lercanadipine, has sufficient bioavailability to impart a therapeutic effect.
Description of the Related Art
Lercanidipine is a dihydropyridine derivative. It is a racemate due to the presence of a chiral
carbon atom at position 4 of the 1,4-dihydropyridine ring.

Chemical name: 3,5-pyridinedicarboxylic acid, 1,4- dihydro-2, 6-dimethyl-4-(3-
nitrophenyl)-2-[(3,3 -diphenylpropyl)methylamino] -1,1 -dimethyl ethyl methyl ester
hydrochloride. MW: 648.2 (free base: 611.7).
Lercanidipine hydrochloride (CAS: 132866-11-6) is a microcrystalline, odourless, citrine powder, readily soluble in chloroform and methanol, practically insoluble in water. Octanol:water partition coefficient (LogP): 6.4.
Lercanadipine hydrochloride is a highly lipophilic dihydropyridine calcium antagonist with long duration of action and high vascular selectivity. Its mechanism of antihypertensive
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activity is attributed to a direct relaxant effect on vascular smooth muscle, which lowers total peripheral resistance. Lercanidipine has been studied in the dosage ranging from 1 to 80 mg. Lercanidipine is normally administered in a dosage of about 10 mg to about 20 mg once or twice daily, the recommended maximum dose being about 30 mg once or twice daily, all available in immediate release tablet form. Lercanidipine is used for treating mild to moderate hypertension and is also expected to be useful in alleviating angina pectoris. It has also been beneficial in elderly patients with isolated systolic hypertension. The recommended starting oral dose of lercanidipine is given by mouth 10 mg once daily before food and is increased, if necessary, after at least 2 weeks to 20 mg daily. Upon oral administration, lercanidipine is absorbed and peak plasma level occurs 1-3 hours following dosage.
By virtue of its high lipophilicity and high membrane coefficient, lercanadipine combines a short plasma half life with a long duration of action. In fact, the preferential distribution of the drug into membranes of smooth muscle cells results in membrane-controlled pharmacokinetics characterized by a prolonged pharmacological effect. In comparison to other calcium antagonists, lercanadipine is characterized by gradual onset and long-lasting duration of action despite decreasing plasma levels. In vitro studies show that isolated rat aorta response to high K.sup.+ may be attenuated by lercanadipine, even after the drug has been removed from the environment of the aortic tissue for 6 hours.
Lercanadipine and its salts, such as the hydrochloride salt, are practically insoluble in water, displaying an aqueous solubility of about 5 microgram/ml. The Lercanadipine is also practically insoluble in acidic media although it has marginally greater insolubility in acidic medium. Even at pH 5 and above, its solubility is less than 20 microgram/ml. Lercanadipine also shows low permeability and is classified as a low permeable drug, as per the guidelines of FDA. Additionally, when administered to patients, lercanadipine displays extensive presystemic first pass elimination as a result of its being a substrate for cytochorme P450 IIIA4 isoenzyme. The combination of poor water solubility, low permeability and considerable first pass metabolism results in low and highly variable bioavailability.
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The absolute bioavailability of lercanadipine is about 10%, because of high first pass metabolism. The bioavailability increases 4-fold when lercanadipine is ingested up to 2 hours after a high fat meal, and about 2-fold when taken immediately after a carbohydrate-rich meal. Consequently, lercanadipine should be taken at least 15 minutes before a meal.
In order to improve the bioavailability of lercanadipine, food is co-administered with each dosage. The administration of food along with lercanadipine has been shown to increase the absorption of lercanadipine significantly and therefore enhance its efficacy, a phenomenon known as "food effect." Studies have shown that simultaneous intake of food (especially food having a high fat content) increases the amount of lercanadipine absorbed between three and four times compared to administration without food. The same studies have shown that lercanadipine administered in the absence of food is not entirely absorbed which results in low and variable bioavailability. The dependence of effective dosing and absorption of lercanadipine upon co-administration of food is inherently undesirable and can result in fluctuations in effectiveness, inter-patient variability, and in poor patient acceptance and/or compliance.
Accordingly, in order to overcome one or more of the foregoing problems, increase the effectiveness of lercanadipine in patients, and provide for more predictable performance of this drug, there is a need in the art for an oral dosage form which affords improved absorption and bioavailability of lercanadipine at a lower maximum plasma concentration Cmax. Particularly, there is a need for an oral dosage form that permits lercanadipine to be administered and absorbed, while reducing or eliminating the food effect. More particularly, there is a need for an immediate release pharmaceutical composition that itself provides rapid absorption of lercanadipine.
Lercanadipine is commercially available from Recordati S.p.A. (Milan, Italy) and has been described along with methods for making it and resolving it into individual enantiomers in U.S. Pat. Nos. 4,705,797; 5,767,136; 4,968,832; 5,912,351; and 5,696,139.
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Drugs that are totally water-insoluble, or are at least poorly water-soluble, are usually characterized by low absorption and poor bioavailability, and present special difficulties when formulating dosage forms. Indeed, it has been reported that the bioavailability of many practically insoluble drugs is limited by their dissolution rates and solubility, which in turn are understood to be controlled by the surface area that they present for dissolution. As such, attempts to improve the bioavailability of these practically insoluble drugs have often focussed on particle size reduction. Strategies for improving apparent solubility and dissolution rate include forming soluble salts for ionizable drugs, reducing crystal size, forming soluble pro-drugs, using amorphous forms, co-solvents and superdisintegrants, impregnating liquid drugs or drug solution in porous powders and using surface active self-emulsifying systems. Although salt formation and particle size reduction are commonly used to increase dissolution rate and oral absorption, there are practical limitations for these techniques. Very fine powders of hydrophobic drugs, on the other hand, are difficult to disperse in water due to the poor wettability of the particle surfaces.
Among the strategies, those that increase dissolution rate of poorly soluble drugs with lipids/surfactants are the most commonly used techniques for enhancing their absorption. Lipid-based self-emulsifying systems are particularly interesting in that they offer both kinetic and thermodynamic enhancement of drug absorption. By forming micelles with the drug substances, lipid molecules may, not only facilitate dissolution, but also increase apparent solubility. It is reasonable to believe that the dissolution or solubilization may further be improved if the drug-lipid matrix is pre-dispersed into micro- or nanometer-size before final formulation. A lipid-based method that facilitates dissolution and, at the same time, achieves manufacturing simplicity gives added advantages.
Inventors of the present invention have been able to overcome the above mentioned problems by incorporation of high HLB surfactant such as Cremophor EL to enhance the solubility and bioavailability of poorly soluble drug Lercanadipine HC1. The drugs in spite of fine particle size (~5 micron) exhibits slow dissolution rates in In vitro dissolution test. However
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significant enhancement in dissolution rate was observed when surfactant was used in the pharmaceutical composition.
SUMMARY OF THE INVENTION
The invention is directed to an immediate release pharmaceutical composition involving surfactants which provides rapid dissolution of the low solubility drug such as lercanadipine or its pharmaceutically acceptable salts. The pharmaceutical composition of the present invention provides rapid release of an effective amount of lercanadipine or its pharmaceutically acceptable salts and at the same time increased permeability resulting in improved absorption over a dose range of 1 to 80 mg. Administration of the pharmaceutical composition of the present invention results in rapid onset of relief from hypertension.
One embodiment of the present invention provides an immediate release pharmaceutical composition comprising lercanadipine, and surfactant.
Another embodiment of the present invention provides an immediate release pharmaceutical composition comprising lercanadipine, and surfactant wherein surfactant is having a high HLB value.
Another embodiment of the present invention provides a immediate release lercanadipine tablets composition in which the lercanadipine is present in the amount sufficient to provide a therapeutic effect when the composition is administered to a patient, e.g., from about 1 to about 80 mg lercanadipine.
In an additional embodiment the present invention provides immediate release solid dosage forms comprising lercanadipine that provide for the in vitro dissolution of more than about 80% of the lercanadipine within the first 60 minutes.
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Yet another aspect of the invention is to provide an immediate release dosage form comprising lercanadipine, and surfactant wherein the dosage form can be tablet or capsule.
Another aspect of the invention is the process for the preparation of solid dosage form comprising a) adsorption of surfactant on to diluents and its sizing, then b) mixing of sized mass with glidant and optionally passing it through roll compactor further sizing, then c) mixing of sized granules with drug and/or excipients like lubricants, disintegrants and d) either compression of lubricated blend into tablets or filling it into capsules.
Another aspect of the invention includes immediate release pharmaceutical composition comprising lercanadipine, and surfactant wherein lercanadipine includes lercanadipine or its pharmaceutically acceptable salts.
Another aspect of the invention is the process of making lercanadipine hydrochloride tablets or capsules prepared by using dry or wet granulation technique or any other suitable technique that is known to the person skilled in the art.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The invention is an immediate release pharmaceutical composition which can be prepared which provides rapid dissolution of the low solubility drug, lercanadipine. The pharmaceutical composition of the present invention provides rapid release of an effective amount of lercanadipine and at the same time increased permeability resulting in improved absorption while retaining an immediate release T.sub.max characteristic over a dose range of 1 to 80 mg. Administration of the pharmaceutical composition of the present invention results in rapid onset of relief from hypertension.
As used herein, the term "immediate release dosage form" means any type of release of the active ingredient, lercanadipine or its pharmaceutically acceptable salts, that provide for the in
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vitro dissolution of at least more than about 80% of the lercanadipine within the first 60 minutes from the composition of the present invention.
The term "dissolution rate" as used herein, refers to the dissolution of an agent over time. The dissolution can be measured as the relative amount of agent dissolved over time, the amount of agent dissolved, or the concentration of the agent. The preferred method of determining dissolution rate is USP basket method at 100 RPM in 900 ml aqueous buffer 0.01N HC1, at 37.degree. C. Alternative methods are equally acceptable including the USP paddle method and other suitable methods known to those of skill in the art.
The term "bioequivalent" means the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study. The term "bioavailability" refers to the rate and extent to which the active ingredient or active moiety, e.g., lercanadipine, is absorbed from a drug product, i.e., tablets, and becomes available at the site of action, i.e., smooth muscle walls of arteries.
Surfactants of the present invention include, but are not limited to anionic and non-ionic surfactants such as sodium lauryl sulfate, poloxamers (copolymers of polyoxyethylene and polyoxypropylene such as polaxomer 188, Polaxomer 407), natural or synthetic lecitins as well as esters of sorbitan and fatty acids, such as Span.RTM. (Commercially available from Sigma-Aldrich Co., St. Louis, Mo.), esters of polyoxyethylenesorbitan and fatty acids, such as Polysorbates or Polysorbate.RTM. (Commercially available from Spectrum Chemical, Gardena Calif.) polyoxyethylated hydrogenated castor oils, such as Cremophor.RTM such as Cremophor EL (Polyoxyl 35 Castor Oil), Cremophor RH40 (Polyoxyl 40 Hydrogenated Castor Oil) or (Commercially available from BASF, Mount Olive, N.J.), polyoxyethylene stearates, such as Myrj.RTM. (Commercially available Myrj 53 and Myrj 59 from Uniqema, New Castle, Del.), Vitamin E TPGS (Eastman Chemical Company, Kingsport, Term.), sucrose monolaurate, sucrose monopalmitate, sucrose monostearate, Gelucire 50/13 (PEG-32
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glyceryl palmitostearate), Gelucrie 50/10 (PEG-32 glyceryl stearate), Gelucire 44/14 (PEG-32 glyceryl laurate), Labrasol (PEG-8 caprylic/capric glycerides) Or any combinations of the surfactants. Preferably the surfactant is a polysorbate and most preferably the surfactant is Polysorbate 80 (Commercially available from Chemical, Gardena Calif.) or Cremophor EL (Polyoxyl 35 Castor Oil) or Cremophor RH40 (Polyoxyl 40 Hydrogenated Castor Oil)
HLB (hydrophilic-lipophilic balance) value is a kind of index numbered from 1 to 20. HLB number or value of a product which is their means of characterizing a particular product with respect to its oil or water solubility.
Pharmaceutically acceptable salts includes lercanidipine hydrochloride, lercanidipine besylate and lercanidipine napadisylate.
The pharmaceutical compositions of the present invention may include additional excipients to improve appearance, handling and processing properties and/or dissolution properties of the active ingredient. Additional excipients contemplated by the present invention include, but are not limited to, carriers, diluents are selected from the group comprising of lactose, mannitol, dibasic calcium phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, calcium sulphate, dextrates, dextrin, sucrose, sorbitol, calcium carbonate, magnesium carbonate, kaolin, maltodextrin, starches, pregelatinized starch and tricalcium phosphate. The disintegrants are selected from the group comprising of crospovidone, croscarmellose sodium, croscarmellose calcium, sodium starch glycolate, low substituted hydroxypropyl cellulose, starch and magnesium aluminium silicate.
Suitable lubricants and/or glidants include, but are not limited to, either individually or in combination, such lubricants and/or glidants as glyceryl behenate (Compritol.TM. 888); metallic stearates (e.g., magnesium, calcium and sodium stearates); stearic acid; hydrogenated vegetable oils (e.g., Sterotex.TM.); talc; waxes; Stearowet.TM.; boric acid; sodium benzoate and sodium acetate; sodium chloride; DL-Leucine; polyethylene glycols (e.g., Carbowax.TM. 4000 and Carbowax.TM. 6000); sodium oleate; sodium benzoate; sodium acetate; sodium
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lauryl sulfate; sodium stearyl fumarate (Pruv.TM.); and magnesium lauryl sulfate and
colloidal silicon dioxide (aerosil).
Additional suitable anti-adherents or glidants include, but are not limited to, either individually or in combination, such anti-adherents as talc, cornstarch, DL-Leucine, sodium lauryl sulfate, and metallic stearates.
The pharmaceutical compositions of the present invention may also contain other optional ingredients that are also typically used in pharmaceutical compositions such as, for example, coloring agents, preservatives, flavorings, and the like.
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Examples
It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the claims appended hereto.
Example 1: Lercanadipine HCL DR tablets 10mg/20mg
Table 1

Sr. No. Ingredient For 10mgstrength Qty/Tab.(mg) For 20mgstrengthQty/Tab.(mg)
1. Lercanadipine HCL 10.0 20.0
2. Cremophor EL (Polyoxyl 35 castor oil) 15.0 30.0
3. Prosolve SMCC 50 (Silicified Microcrystalline cellulose) 100.0 200.0
4. Aerosil 200 (Colloidal silicon dioxide) 4.0 8.0
5. Plasdone S630 (Copovidone) 10.0 20.0
6. Polyplasdone INF 10 (Crospovidone) 10.0 20.0
7. Microcel -500 (Microcrystalline cellulose) 87.0 174.0
8. Polyplasdone INF 10 (Crospovidone) 10.0 20.0
9. Talc 2.0 4.0
10 Magnesium stearate 2.0 4.0
Total (mg) 250.0 500.0
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Brief manufacturing procedure:
1. Cremophor EL was adsorbed onto the Weighed quantity of Prosolve SMCC 50 (#30 sieve).and mixed for 5 minutes. The blend thus obtained was then sifted through #30seive.
2. The weighed quantity of Aerosil 200 (through #60 sieve), Plasdone S630 and Polyplasdone INF-10 (through #30seive) was mixed with the blend of step 1.
3. The blend from step 2 is then passed through Roll compacter, and the roll compacted material was then sifted through #24 sieve.
4. Weighed quantity of Lercanadipine HCl, Microcel 500 and Polyplasdone INF-10 were sifted through #30 sieve and then mixed with the granules of step 3.
5. Talc sifted through #60seive then mixed well with blend of step 4 for 5 minutes.
6. Magnesium stearate sifted through #60seive then added to the blend of step 5 and mixed for 2 minutes.
7. The lubricated granules of step 9 were then compressed into tablets using suitable punches.
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Claims:
1. An immediate release solid dosage form comprising about 1 mg to 80 mg of lercanidpine or its pharmaceutically acceptable salts and surfactant.
2. An immediate release solid dosage forms according to claim 1 wherein solid dosage form is a tablet or a capsule.
3. The immediate release solid dosage form according to claim 1 wherein the solid oral dosage form releases in-vitro the lercanidipine at a rate of more than about 80% within the first 60 minutes following entry of the solid oral dosage form into a use environment.
4. The immediate release solid dosage form according to claim 1, wherein the lercanidipine is selected from the group consisting of lercanidipine hydrochloride, lercanidipine besylate and lercanidipine napadisylate.
5. The immediate release pharmaceutical composition of claim 1, wherein the surfactant is selected from the group comprising of sodium lauryl sulfate, poloxamers (copolymers of polyoxyethylene and polyoxypropylene such as polaxomer 188, Polaxomer 407), natural or synthetic lecitins as well as esters of sorbitan and fatty acids, such as Span.RTM. (Commercially available from Sigma-Aldrich Co., St. Louis, Mo.), esters of polyoxyethylenesorbitan and fatty acids, such as Polysorbates or Polysorbate.RTM. (Commercially available from Spectrum Chemical, Gardena Calif.) polyoxyethylated hydrogenated castor oils, such as Cremophor.RTM such as Cremophor EL (Polyoxyl 35 Castor Oil), Cremophor RH40 (Polyoxyl 40 Hydrogenated Castor Oil) or (Commercially available from BASF, Mount Olive, N.J.), polyoxyethylene stearates, such as Myrj.RTM. (Commercially available Myrj 53 and Myrj 59 from Uniqema, New Castle, Del.), Vitamin E TPGS (Eastman Chemical
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Company, Kingsport, Term.), sucrose monolaurate, sucrose monopalmitate, sucrose monostearate, Gelucire 50/13 (PEG-32 glyceryl palmitostearate), Gelucrie 50/10 (PEG-32 glyceryl stearate), Gelucire 44/14 (PEG-32 glyceryl laurate), Labrasol (PEG-8 caprylic/capric glycerides) Or any combinations of the surfactants. Preferably the surfactant is a polysorbate and most preferably the surfactant is Polysorbate 80 (Commercially available from Chemical, Gardena Calif.) or Cremophor EL (Polyoxyl 35 Castor Oil) or Cremophor RH40 (Polyoxyl 40 Hydrogenated Castor Oil)
6. An immediate release oral dosage form comprising (i) lercanidipine, (ii) surfactant, (iv) a lubricants and/or glidants and (iv) optionally, a film coating.
7. The immediate release solid dosage form according to claim 5, wherein the lercanidipine is selected from the group consisting of lercanidipine hydrochloride, lercanidipine besylate and lercanidipine napadisylate.
8. The immediate release pharmaceutical composition of claim 5, wherein the surfactant is selected from the group having high HLB value.
9. The immediate release pharmaceutical composition of claim 5, wherein the lubricants and/or glidants is selected from the group lubricants and/or glidants as glyceryl behenate (Compritol.TM. 888); metallic stearates (e.g., magnesium, calcium and sodium stearates); stearic acid; hydrogenated vegetable oils (e.g., Sterotex.TM.); talc; waxes; Stearowet.TM.; boric acid; sodium benzoate and sodium acetate; sodium chloride; DL-Leucine; polyethylene glycols (e.g., Carbowax.TM. 4000 and Carbowax.TM. 6000); sodium oleate; sodium benzoate; sodium acetate; sodium lauryl sulfate; sodium stearyl fumarate (Pruv.TM.); and magnesium lauryl sulfate and colloidal silicon dioxide (aerosil).
10. Process for the preparation of immediate release solid oral dosage form comprising a) adsorption of surfactant on to diluents and its sizing, then b) mixing of sized mass with
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glidant and optionally passing it through roll compactor further sizing, then c) mixing of sized granules with drug and/or excipients like lubricants, disintegrants and d) either compression of lubricated blend into tablets or filling it into capsules.
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