Specification
FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION (See section 10, rule 13)
FORMULATION OF HIV PROTEASE INHIBITOR"
EMCURE PHARMACEUTICALS LTD.,
R&D Centre, T-184, MIDC, Bhosari, Pune 411026, Maharashtra, India
The following specification particularly describes the invention and the manner in which it is to be performed.
FIELD OF THE INVENTION
The present invention relates to a pharmaceutically useful composition comprising at least one protease inhibitor and to a process for preparation of such pharmaceutical compositions.
BACKGROUND OF THE INVENTION
The development of human immunodeficiency virus (HIV) protease inhibitors has been one of the most significant advances of the past decade in controlling HIV infection. Since the clinical introduction of protease inhibitor therapy as part of highly active antiretroviral therapy (HAART), there has been a dramatic decline in AIDS-related morbidity and mortality. Protease Inhibitors are a class of anti-HIV drugs, which prevent T-cells that have been infected with HIV, from producing new copies of the virus by preventing protease enzyme function.
Therapeutically and commercially useful Protease inhibitors include Amprenavir (US 5,585,397), Tipranavir (US 5,852,195), Indinavir (US 5,413,999), Saquinavir (US 5,196,438), lopinavir/ritonavir (US 5,541,206), Fosamprenavir (US 6,436,989), Darunavir (US 5,843,946), Atazanavir (US 5,849,911) and Nelfinavir (US 5,484,926).
Currently, most of the protease inhibitors, because of their poor solubility, are available worldwide in the form of soft gelatin capsule containing a fill solution in which the active ingredient is dissolved.
The prior art approaches to improve the solubility of Protease inhibitor and presenting them in the form of gelatin capsule has several limitations as follows:
i) Only a limited amount of protease inhibitor can be dissolved in these dosage
forms, which therefore limits the amount of protease inhibitor that can be loaded in each gelatin capsule;
ii) As a result of limited drug loading in each capsule, a number of capsules must be administered to a patient in need of it, in order to achieve necessary therapeutic concentration of the Protease inhibitor. For example, the
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recommended oral dose for adult of Amprenavir, which is available as a 50 mg capsule, is 1200 mg twice daily. Therefore, a patient needs to ingest 24 capsules of Amprenavir each time. Similarly, a patient on Ritonavir therapy needs to ingest 12 capsule per day and 360 capsules in a month. The agony of the patient is further amplified because of extremely large number of capsules to be ingested and therefore the therapy turn out to be very cumbersome for a patient and often leads to patient non-compliance and discomfort;
iii) Further, therapy for HIV patients include multiple medications such as other Protease inhibitor or antiviral agents, antibiotics and lipid lowering agents to control opportunistic infections and other disease or conditions they may be afflicted with. As a result, these patients require to consume an extraordinary number of medications in a variety of different dosage forms in a given dosing period;
iv) Extraordinary number of medications not only increases the bio-burden of a patient, but also increase the possibility of consumption of improper dose of therapeutic agent;
v) Further, to increase the bioavailability of Protease inhibitor, it is often recommended that patient should swallow the gelatin capsule formulation following the meal to increase the overall bioavailability of the therapeutic agent. Bioavailability of Protease inhibitor, further, can vary with the fat content of the meal. Therefore, manufacturers of most of the Protease inhibitor recommend that such formulation needs to be administered after meal having limitation of low fat content, and such limitation can lead to patients non-compliance;
vi) The antiviral regimen therapy is further complicated by the fact that some of the dosage forms, which has drug in solution form, for example capsule formulation of Saquinavir, Tipranavir etc., require refrigerated storage conditions to prevent degradation of the active agent; and
vii) Many pharmaceutical agents useful in treatment of HIV such as Protease inhibitor have bitter taste. Therefore, a gelatin capsule formulation having an unimproved taste discourages patient from complying with their drug taking regimens.
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Generally, aqueous solubility of a poorly water soluble drug in a pharmaceutical composition is known to be improved by micro-pulverization of the drug and/or transformation of the drug into a derivative thereof. However, in the case of Protease inhibitor micro-pulverization does not help to achieve desired solubility and transformation into a derivative might result in unwanted changes in pharmaceutical effect.
Various other attempts which are have also been reported in this direction, which are as follows:
a) Rosenberg el. al. in published applications, US 2005/0084529 and US 2005/0143404 disclose a pharmaceutical composition containing an undissolved form of a PI. The disclosed formulations comprises of solid dispersion of at least one protease inhibitor in at least one pharmaceutically acceptable water-soluble polymer and at least one pharmaceutically acceptable surfactant. The preferred pharmaceutically acceptable water soluble polymer has a glass transition temperature of at least about 50° C. Further, melt-extrusion is disclosed as preferred method for preparation of solid dispersion of Protease inhibitor;
b) In another application, US 2005/0048112, Breitenbach el. al. also disclose a solid pharmaceutical dosage forms comprising solid dispersions of protease Inhibitor or combination thereof in at least one pharmaceutically acceptable water-soluble polymer and at least one pharmaceutically acceptable surfactant;
c) Pacheco el. al. in US 2005/0250764 disclose a process for preparation of a concentrated pharmaceutical composition of Ritonavir by using a mixture of alcoholic solvent and co-solvent of C2-C4 (propylene glycol), a mixture of median chain mono/diglycerides of Cg-Cio, a pharmaceutically suitable surfactant and an antioxidant. The document further discloses that by using such compositions, it is possible to produce gelatin capsules of delivering amounts of 200 mg or 300 mg of Ritonavir, which would reduce the dosage administration for 6 or even 4 capsules per day;
the above mentioned and various other efforts made in the art to overcome the limitations associated with capsule or liquid formulation of Protease inhibitor. Most of these approaches could be categorized into three groups as follows:
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a) Preparation of solid dispersion formulation of Protease inhibitors;
b) Utilization of co-solubilizing agent or penetration enhancer or natural agent to enhance the solubility of Protease inhibitors; and
c) Preparation of porus matrix
However, all the abovementioned approaches suffers from one or more of the following limitations:
Solid solutions/dispersions are preferably produced by a melt-extrusion method. An important prerequisite to manufacture solid solutions/dispersions by this method is miscibility of the drugs and the carriers in the melt forms. Another limitation to the melt method is the thermo-instability of the drugs and carriers.
Further, the solid dispersions prepared by melt-extrusion method require utilization of water soluble excipients as carriers of solid solutions/dispersions. An ideal carrier should possess good solubility in water, low melting points, ability to solubilize active agents and capacity to improve wettability of therapeutic agent. Though, there exists a number of carrier, which could be utilized for preparation of solid dispersion, however, it is generally very difficult, if not impossible, to select an ideal carrier which has all abovementioned ideal properties. Further, other limitations associated with melt extrusion method such as method of preparation, reproducibility of its physicochemical properties, formulation into suitable dosage forms, physical and chemical compatibility of the ingredients and active agents at the melting temperature, scale-up of manufacturing processes and physical and chemical stability of drugs and vehicles further aggravates manufacturer concern for taking recourse to such a method and make such method not particularly commercially viable.
Recourse to utilization of co-solubilizing agent, penetration enhancer hardly provides any help to solve any or all of the above mentioned limitation with respect to gelatin capsule formulation.
The porous matrix formulation has a major disadvantage that the process to prepare such a formulation is complex. Generally, for forming porous matrix, drug is first dissolved in suitable volatile solvent to form a drug solution. Then such drug solution is combined with at least one pore forming agent with the drug solution to form an emulsion, suspension or
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second solution. Then volatile solvent and pore forming agents are removed to give porus matrix of drug, which then processed using standard techniques into tablet or capsules. However, improvement achieved in solubility of active agent by formation of such a matrix is particularly not suitable to form a tablet formulation for Protease inhibitor particularly and render such method of academic interest only.
Further, none of the tablet formulations disclosed above make any attempt to improve the disintegration time of the formulation. A generally accepted maxim is that for a drug to be readily available to the body, it must be in solution. For most tablets, the first important step toward solution is breakdown of the tablet into smaller particles or granules.
Therefore, a need exists for an improved pharmaceutical composition of Protease inhibitor, which would not only be free from most, if not all, the aforementioned limitations but also simple, convenient, economical, rapidly disintegrating, room temperature stable, patient compliant, commercially viable and would have improved bioavailability.
OBJECTS OF THE INVENTION
An object of the present invention is to provide a novel pharmaceutical composition comprising at least a protease inhibitor.
A still further object of the present invention is to provide a process for preparation of
novel solid pharmaceutical composition comprising at least one protease inhibitor and has improved bioavailability.
SUMMARY OF THE INVENTION
The present inventors have found that all the abovementioned objectives could be achieved by preparing a novel dosage formulation comprising at least one protease inhibitor.
The present invention provides compositions containing Protease inhibitor and a variety of other excipients characterized in that the active agent is processed by using judiciously selected excipients. By taking recourse to such a method the dissolvability of said protease
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inhibitor can be drastically enhanced rendering such solid dispersion composition suitable for preparation of solid pharmaceutical composition.
In an aspect, the drug (protease inhibitor) and excipients are processed for preparation of granules. Typically, granules are prepared by granulation process, wherein the active agent is first adsorbed onto a surface of excipients and then the mixture is converted into granules. By utilizing such an adsorption type granulation technique for preparation of a dosage formulation, the method is free of disadvantages and limitations of others known method in the art, such as hot melt solid dispersion, for the preparation of solid dispersions.
In another embodiment, the present invention provides a dosage formulation of protease inhibitor, wherein the total weight of tablet is substantially reduced. The judicious selection of excipients according to present invention helps to achieve at least 20 - 30% reduction in the weight when compared to the marketed formulation of the same amount of active agents.
In yet another preferred embodiment, the present invention provides a dosage formulation of protease inhibitor, which has a very low disintegration time and thereby, could improve the bioavailability of the poorly soluble protease inhibitor. By rapid disintegration, the drug is released faster in the GI fluid and thus is available easily and far more rapidly for absorption.
In still another embodiment, the solid pharmaceutical composition of the present invention involves judicious selection of the excipients. The active agent is adsorbed onto the surface of excipients and then converted into granules. The obtained granules then may be compacted to get a compressed tablet.
In still further aspect, the granules prepared from adsorbing a protease inhibitor, could be mixed with granules of another protease inhibitor, prepared either by same process or by any conventional process, to get a solid pharmaceutical composition comprising two or more protease inhibitor.
These and other objects of the present invention will become more fully apparent from the following detailed description and appended examples.
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DETAILED DESCRIPTION OF THE INVENTION:
The present invention provides a pharmaceutical composition comprising at least one protease inhibitor. In one embodiment, the solid pharmaceutical composition is formed from adsorbing active agents onto surface of judiciously selected adsorbing excipients.
In the context of the present invention, the term protease inhibitor means the substances which inhibit function of protease enzyme. Typical example of such agents includes, but not limited to, Amprenavir, Tipranavir, Indinavir, Saquinavir, Lopinavir, Ritonavir, Fosamprenavir, Darunavir, Atazanavir and Nelfinavir. The preferred protease inhibitors according to the present invention are Ritonavir and Lopinavir. The highly preferred protease inhibitor is Lopinavir and ritonavir.
The term adsorbing excipients, or excepient capable of adsorption is any pharmaceutically acceptable excipient, which is capable of adsorbing the protease inhibitor onto its surface. For adsorbing protease inhibitor, typically, any natural or synthetic polymer could be used. Among such polymer are pH-dependent polymers, pH-independent polymers and water soluble polymers. Typical examples of such polymers include, but are not limited to, cellulose derivatives, polyethylene glycols, polyvinyl polymers, polyacrylates, polymethacrylates, sugar derivatives, polyols and their polymers, urea, organic acids and their derivatives, and combinations of the forgoing.
Typically, for adsorption of protease inhibitor, according to present invention, polyethylene glycols with molecular weight of 1500 - 20,000 are preferred. The aqueous solubility of polyethylene glycols decreases with molecular weight whereas the viscosity increases with increase in molecular weight. From the polyvinyl group polymers, poly vinyl pyrrolidone, polyvinyl alcohol, crospovidone, polyvinyl pyrrolidone - polyvinyl acetate copolymer are preferred. Among cellulose derivatives, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl
cellulose phthalate, microcrystalline cellulose is preferred. Examples of suitable acrylic polymers include polymethyl methacrylate, polyethyl methacrylate, polybutyl methacrylate, polyisobutyl methacrylate, polyhexyl methacrylate, polyphenyl methacrylate, polymethyl acrylate, polyisopropyl acrylate, polyisobutyl acrylate, polyoctadecyl acrylate. Urea, sugar such as mannitol, cholesterols, gelatin, starch,
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processed starch, phospholipids, etc. could also be employed for adsorption of active agent.
Abovementioned polymers could be used independently, or if necessary, in a combination of two or more species. The compounding ratio of drug to the polymer can depend on drug and particular polymer used for the adsorption of drug, the desired relase profile etc. Typically, it could vary from 0.1 to 99.9%.
Typically, when Lopinavir is used as protease inhibitor, then microcrystalline cellulose is the preferred adsorbing agent. The preferred amount of microcrystalline cellulose in case of Lopinavir varies from about 1 to 5 parts of drug amount. The highly preferred amount being 2 to 3 parts of drug amount, which can further be increased based on the desired dissolution profile.
Typically, for adsorbing the active agent onto surface of excipient, the active agent is first dissolved in a suitable solvent. The solution thus formed is slowly added to a suitable excipient and is then dried. During drying the solvent gets evaporated or removed and the active agent is uniformly adsorbed onto the surface of excipients.
The solid mass resulting from the adsorption of active agent onto the surface of excipient is milled or grounded to get granules, pellets, beads, spherules, beadlets, millispheres, microspheres, nanaospheres etc. Preferably, the solid mass is milled to granules. The granules may then be compacted with usual compressing tools such as tablet press to get a compacted tablet.
The granules prepared by above method may then additionally be combined with the granules of any other active agents such as protease inhibitors, prepared by either same method or by any other suitable conventional method such as dry granulation, wet granulation or direct compression and by using suitable excipients that are normally employed in such pharmaceutical compositions, the only qualifications being that the excipients must not deleteriously affect the stability and intend of the pharmaceutical composition.
The granules of such two or more drugs may then be mixed together to get a homogeneous mixture, which is then compressed with suitable excipients to get a compressed tablet.
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Optionally, the granules of different active agents may be processed in such a way to get a dosage form consisting of plurality of layers of active agents for example laminated or multiple layer tablets. They can be in open or closed form. Closed dosage from are those in which one layer is completely surrounded by at least one other layer. In a highly preferred embodiment, bi-layer tablet is the preferred pharmaceutical dosage form, when the granules of two different active agents are compressed together.
At least one additive selected from flow regulators, disintegrants, bulking agents, lubricants, and surfactants may be employed in compressing the granules.
Suitable flow regulators are selected from highly dispersed silica, and animal or vegetable fats or waxes.
Suitable disintegrating agents illustratively include, but are not limited to, either individually or in combination croscarmellose sodium, sodium starch Glycollate, cross-linked polyvinylpyrrolidone, cross-linked carboxymethyl starch, starches and microcrystalline cellulose, magnesium aluminium silicate, polyacrylin potassium. The disintegrant can be present in the formulations in an amount of about 0.01 to about 10 weight percent of the total weight of the formulation. Typically, crospovidone is preferred as a disintegrant.
Suitable bulking agents illustratively include, but are not limited to, either individually or in combination, lactose, including anhydrous lactose and lactose monohydrate, starches, including directly compressible starch, starch 1500 and hydrolyzed starches, sugars such as sucrose, mannitol, sorbitol, xylitol, dextrose dextrin, dextran, maltodextrin and dextrose monohydrate, dibasic calcium phosphate dihydrate, calcium carbonate, calcium phosphate and/or hydrogen phosphate, celluloses including microcrystalline cellulose, food grade sources of alpha-and amorphous cellulose powdered cellulose, hydroxypropylcellulose (HPC) and hydroxypropyl methylcellulose (HPMC).
Combination of two or more bulking agents can be used in the dosage formulations. When used, the total amount of bulking agents can be up to about 99 weight percent of the total weight of the formulation; specifically about 20 to about 98 weight percent; more specifically about 50 to about 75 weight percent. Typically, microcrystalline cellulose is preferred as bulking agent.
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A lubricant can also be used in the dosage formulations to aid in the processing of powder materials. Exemplary lubricants include calcium stearate, glycerol behenate, magnesium stearate, mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, talc, vegetable oil, zinc stearate, and combinations thereof.
Suitable surfactants illustratively include, but are not limited to, either individually or in combination ionic surfactants, such as sodium lauryl sulphate or non-ionic surfactants such as different poloxamers (polyoxyethylene and polyoxypropylene copolymers), natural or synthesized lecithins, esters of sorbitan and fatty acids, esters of polyoxyethylene sorbitan and fatty acids, polyoxyethylated hydrogenated castor oil, polyoxyethylene stearates, dimethylpolysiloxane or any combination of the above mentioned surfactants.
The tablet formulation thus prepared can also be film coated. Typically, film coat concentration can be varied up to about 10% to complement the drug amount, and preferably about 2.0% to about 5.0%. Film coating suspensions typically includes film forming agents, plasticizer, colorants etc. However, any specific agent could be added to the coating solution based on the desired properties of the tablet. Coating solution generally include combinations of one or more of the following components: carboxymethylcellulose sodium, carnauba wax, cellulose acetate phthalate, cetyl alcohol, confectioner's sugar, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, liquid glucose, maltodextrin, methyl cellulose, microcrystalline wax, Opadry and Opadry II, polymethacrylates, polyvinyl alcohol, shellac, sucrose, talc, titanium dioxide, and zein.
In another aspect, the present invention also provides a novel process for the processing of the drug, excipient and other components to get active agent adsorbed onto the surface of excipient. The process, according to present invention, comprises of following steps:
1. dissolving a first protease inhibitor in an organic solvent;
2. adding and mixing slowly clear solution or suspension of step -(1), to an adsorbing excipient to obtain a solid mass;
3. milling the solid mass and drying to obtain granules;
4. compressing the granules of step ~(3), optionally with additional pharmaceutically acceptable excipients, to obtain a tablet;
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5. optionally obtaining granules of a second protease inhibitor by repeating steps (1) to (3) or by conventional methods, and mixing the granules of step -(3), with granules of second protease inhibitor alongwith excipients to obtain a tablet.
Further various solvent could be employed to dissolve the active agent so that when mixed with a suitable excipient and dried, the active agent gets adsorbed onto the surface of the same excipient. The choice of the solvent would be determined by the solubility of the active agent. Various solvent that could be employed may be selected from organic as well as inorganic solvent. The organic solvents can be selected from the group consisting of chloroform, isopropyl alcohol, methylene chloride, acetone, ethanol. methanol and the like or mixtures thereof.
By using the process referred above, the oral pharmaceutical composition comprising one protease inhibitor may be prepared. By using the methods of the present invention, the primary advantage is in the reduction of the tablet size. For example, a commercially available unit dose combination tablet of ritonavir (50 mg) and lopinavir (200 mg) weighs approximately 1250 mg when manufactured by using hot melt extrusion method. The judicious selection of the excipients and the process of manufacturing according to present invention can provide a tablet of ritonavir (50 mg) and lopinavir (200 mg) weighing just about 900 mg.
Thus, in one embodiment, by present invention, a reduction of about 20% is achieved, which means that the patient is exposed to reduced amount of excipients and thereby reduces the bio-burden of the patient and hence could lead to better patient compliance. Such a lowering of tablet weight also translates into a thinner, smaller tablet. Because, especially in antiretroviral therapy, many high dose tablets has relatively large size and the ability to decrease the size can be very advantageous. A smaller tablet is visually more appealing and especially, easier to swallow. The marketed tablet has a thickness of about 7.6 to 7.8 mm, whereas the tablet formulation prepared according to present invention results in a thickness of about 5.3 to 5.4 mm only. Thus by reduced size, the present invention helps to avoid trauma of the patients, which one feels while administering a voluminous tablet.
Further, in another embodiment, the present invention provides a tablet comprising protease inhibitor capable of quick disintegration in the oral cavity. For e.g. a compressed
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tablet of ritonavir-lopinavir combination, prepared according to present invention disintegrates in a very short period of time, typically less than 10 minutes, preferably within 3 to 5 minutes. The disintegration time is very low when compared with a commercially available tablet formulation of ritonavir/lopinavir combination, which disintegrates in about 50 -60 minutes, when tested using standard protocols known in the art for evaluation of disintegration time. Such a rapid disintegration of tablet is highly critical to the subsequent dissolution and bio-availability, particularly for hydrophobic drugs like protease inhibitors. Rapidly disintegrating tablet can attain a high dissolution rate and which in turn is capable of imparting improved bioavailability for the formulation.
The principles, preferred embodiments, and modes of operation of the present invention have been described in the foregoing specification. The invention which is intended to be protected herein, however, is not to be construed limited to the particular forms disclosed, since these are to be regarded as illustrative rather than restrictive. Variations and changes may be made by those skilled in the art, without departing from the spirit of the invention.
Some of the advantages of the invention include:
- providing a formulation having better onset and bioavailability
- providing a formulation having improved dissolution profile complying with pharmacoepial standards
- providing a formulation wherein the number of capsules to be consumed by the patient is far less as compared to current products
- providing a formulation which can be produced by a simple, economical process
providing a formulation comprising protease inhibitor, which is rapidly disintegrating, stable at room temperature, provides improved patient compliance and is commercially viable.
The invention and various accompanying advantages of the present invention is further explained with the help of following illustrative examples, however, in no way these examples should be construed as limiting the scope of the invention. Tablets of different strengths and doses, as known in the art, can be prepared by varying the quantities of excipients, proportionately, with respect to the amount of active ingredient. Hence any embodiment that may be apparent to a person skilled in the art, with respect to the following example is deemed to fall within the scope of the present invention.
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EXAMPLES:
Example-1: Preparation of tablets containing ritonavir and lopinavir
Step A: Preparation of Lopinavir Granules:
Lopinavir granules are prepared by using the methods as disclosed in the present invention i.e. by adsorbing the active agent onto a surface of an excipient. The active agent, lopinavir
(200 mg), is dissolved in mixture of isopropyl alcohol and methylene chloride solution. This solution is slowly added to the microcrystalline cellulose (450 mg). The obtained wet
mass is milled, and then dried to get the constant weight mass. During drying, the organic solvent gets evaporated and the active agent is adsorbed onto the surface of microcrystalline cellulose. The dried granules are then sifted and sized to get the desired particle size granules.
Step B: Preparation of Ritonavir Granules:
Sift the Ritonavir (50 mg), microcrystalline cellulose (135 mg) to get the particles of desired size. Then by using polysorbate 20 and povidone processed the ritonavir and microcrystalline cellulose by wet granulation method to get the granules of the desired size. Mill the wet mass and dry the solid mass till a constant weight mass is achieved. Sift the above granules and mill the oversized granules to get the granules of suitable size.
Step C: Tablet Compression:
Transfer the above prepared granules of lopinavir and ritonavir, sifted lubricant and
surfactant to the planetary mixer and blend at slow speed to get the homogenous mixing. Feed the above blend to the tablet compression press and compress the granules by using conventional compressing machine.
Step D: Coating of Tablet:
Above prepared tablet is further subjected to film coating process by using conventional coating pan apparatus. Opadry® solution is used to coat the tablet.
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Example- II
Comparison of the ritonavir/lopinavir tablet prepared according to present invention with commercially available formulation of ritonavir/lopinavir
The ritonavir / lopinavir tablet is prepared by following exact procedure as disclosed in
Example- 1. the prepared tablet is then evaluated for various tablet properties such as weight, thickness, hardness, disintegration time friability by using standard procedures known in the art. The obtained results are then compared with a commercially available tablet formulation of ritonavir/lopinavir. There is a product available in the market called "Kaletra" which is a combination of ritonavir and lopinavir. The comparison is with respect to this product. The results of this study is summarized in Table -I.
Table -I: Comparison of ritonavir / lopinavir tablet properties according to present invention with that of marketed formulation
Sr. No Properties Tablet according to present invention Marketed tablet
1 Average weight (mg) 900 1250
2 Thickness (mm) 5.3-5.4 7.6-7.8
3 Hardness (kg) 19.2 24
4 Disintegration time (with disc) 2-3 min > 50 min
5 Friability (%) 0.08 -
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Claims:
1. An oral pharmaceutical composition comprising at least one protease inhibitor, wherein the said pharmaceutical composition is prepared by granulation process.
2. An oral pharmaceutical composition comprising at least one protease inhibitor, wherein the said pharmaceutical composition has disintegration time of less than 10 minutes when tested with conventional USP device.
3. An oral pharmaceutical composition of protease inhibitor comprising at least one protease inhibitor and excipients, capable of adsorbing the protease inhibitor.
4. A pharmaceutical composition as claimed in claim 3, wherein the excipients is microcrystalline cellulose.
5. A pharmaceutical composition as claimed in any of claims -1 to 3, wherein the protease inhibitor is selected from Amprenavir, Tipranavir, Indinavir, Saquinavir, Lopinavir. Ritonavir, Fosamprenavir, Darunavir, Atazanavir and Nelfinavir or combinations thereof.
6. A pharmaceutical composition as claimed in claim 5, wherein the protease inhibitor is a combination of ritonavir and lopinavir.
7. A process for preparation of a oral pharmaceutical composition comprising at least one protease inhibitor comprising the steps of:
i) dissolving a first protease inhibitor in an organic solvent;
ii) adding and mixing slowly clear solution or suspension of step (i), to an
adsorbing excipients to obtain a solid mass;
iii) milling the solid mass and drying to obtain granules;
iv) compressing the granules of step (iii), optionally with additional
pharmaceutically acceptable excipients, to obtain a tablet;
v) optionally obtaining granules of a second protease inhibitor by repeating
steps (i) to (iii) or by conventional methods, and mixing the granules of
step (iv), with granules of second protease inhibitor along with excipients
to obtain a tablet.
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8. A pharmaceutical composition comprising at least one protease inhibitor prepared according to claim 7.
9. A solid pharmaceutical composition of protease inhibitor as described herein with respect to foregoing examples.
10. An oral pharmaceutical composition comprising at least one protease inhibitor, substantially as described herein with reference to the foregoing examples.
Dated this 23rd day of November, 2006
VIBHA SHUKLA
OF K&S PARTNERS
ATTORNEY FOR THE APPLICANTS
ABSTRACT
"FORMULATION OF HIV PROTEASE INHIBITOR"
The present invention relates to a pharmaceutically useful composition comprising at least one protease inhibitor and to a process for the preparation of such pharmaceutical compositions, wherein the said pharmaceutical composition is prepared by granulation process.
