WO2009153654A1

WO2009153654A1 - Solid dosage forms of antiretrovirals

Info

Publication number: WO2009153654A1
Application number: PCT/IB2009/006008
Authority: WO
Inventors: Ravindranath Gampa; Udaya Kumar Dude; Kalika Reddy Alla; Nagaprasad Vishnubhotla; Sivakumaran Meenakshisunderam
Original assignee: Aurobindo Pharma Limited
Priority date: 2008-06-17
Filing date: 2009-06-15
Publication date: 2009-12-23

Abstract

The present invention relates to a solid oral dosage forms comprising lopinavir, ritonavir, water soluble polymer and surfactant prepared by a process comprising the steps of: a) blending lopinavir, ritonavir and one or more excipients, b) heating a surfactant to about 50-800C to form a clear transparent solution, c) spraying the surfactant solution of step (b) on the blend of step (a), d) blending the material of step (c) with water soluble polymer and e) processing the blend of step (d) into a solid dosage form.

Description

SOLID DOSAGE FORMS OF ANTIRETRO VIRALS Field of the invention The present invention relates to solid oral dosage forms comprising lopinavir and ritonavir prepared by an improved process.

Background of the invention

Acquired Immunodeficiency Syndrome (AIDS) and related diseases caused by human immunodeficiency virus (HIV) is a major health problem worldwide. It is the condition in human in which the immune system begins to fail, leading to life-threatening opportunistic infections. To overcome this deadly disease many antiretroviral drugs are developed which include HIV protease inhibitors (Pi's), nucleoside/nucleotide reverse transcriptase inhibitors (NRTI' s) and non-nucleoside reverse transcriptase inhibitors (NNRTFs). Most of the available dosage regimens for the treatment of HIV require combination of these drugs.

Lopinavir and ritonavir belongs to the class of protease inhibitors. Lopinavir is chemically known as [lS-[lR*,(R*),3R*,4R*]]-N-[4-[[2,6- dimethylphenoxy)acetyl]amino]-3-hydroxy-5-phenyl-l-(phenylmethyl)pentyl] tetrahydro-α-(l-methylethyl)-2-oxo-l(2H)-pyrimidineacetamide and ritonavir is chemically known as 10-hydroxy-2-methyl-5-(l-methylethyl)-l-[2-(l- methylethyl)-4-thiazolyl]-3,6-dioxo-8, 1 l-bis(phenylmethyl)-2,4,7, 12-tetraazatri decan-13-oic acid, 5-thiazolylmethyl ester,[5S-(5R*,8R*,10R*,HR*)].

Ritonavir is marketed under trade name Norvir® in United States in the form of oral solution and capsule as well as in combination with lopinavir under the trade name Kaletra® in the form of oral solution, capsule and tablet. The

200/5 Omg tablet dosage form of Kaletra® has been approved by FDA in October

2005 and 100/25mg tablet dosage form in November 2007.

Most of the protease inhibitors such as lopinavir, ritonavir, nelfmavir and indinavir are less bioavailable due to poor water solubility and hence difficult to formulate. Dosage forms for these products are prepared by dissolving the drug in a solvent and further processed into liquid formulation or liquid filled soft gelatin capsule in which the drug is properly dissolved. To overcome the disadvantages associated with soft gelatin capsule such as drug loading capacity, variability of drug and need for refrigeration, hard gelatin capsule and tablet formulations have been developed. Even though lopinavir and ritonavir are low soluble and permeable, the particle size reduction or crystal form will not have a significant impact on the dissolution or bioavailability of the tablet dosage form. The currently available tablet dosage form is formulated using hot melt extrusion (Meltrex) technology, which helps in increasing the bioavailability by dispersing the active ingredient in molecular level. Moreover, this technology is advantageous over conventional technologies by suspending the drug particles to deaggregate in the polymer melt due to intense mixing and agitation and also by allowing high drug loading. This technology is disclosed in US 2005/0143404, US 2005/0084529, US 2005/0048112 and US 2007/0249643 wherein the composition comprises lopinavir and ritonavir, water soluble polymer and surfactant, comprising the steps of (a) preparing a mixture of combination of HIV protease inhibitors, a water soluble polymer and a surfactant, (b) feeding the mixture in a twin screw extruder while maintaining a high temperature to form a homogenous melt and (c) finally compressing the dried melt to form a tablet. US 7,364,752 discloses a solid dispersion comprising HIV protease inhibiting compound prepared by dissolving or dispersing the HIV protease inhibiting compound in a sufficient amount of an organic solvent followed by dispersion into a suitable water soluble carrier. The solvent is then evaporated followed by cooling, leaving the drug dispersed or dissolved in the molten matrix.

WO 2006/037827 discloses a composition comprising ritonavir and a compound enabling gastrointestinal fluid to penetrate that composition which is selected from the group comprising silicates and silica oxide and further discloses a process, which comprises a kneading step in which the speed and the time of addition of the solvent is thoroughly controlled. WO 2008/009689 discloses a composition comprising active ingredients including lopinavir and ritonavir along with at least one pharmaceutically acceptable polymer and a solubilizing composition comprising at least one tocopheryl compound having a polyalkylene glycol and at least one alkylene glycol fatty acid monoester, wherein the composition is prepared by homogeneous melting of active ingredients, polymers and solubilizing composition and allowing the melt to solidify to obtain a solid dispersion.

WO 2008/017867 discloses a composition comprising one or more antiretroviral drugs including lopinavir and ritonavir or their pharmaceutically acceptable salts, solvates or hydrates and at least one water insoluble polymer prepared by various methods such as melt granulation, melt extrusion, spray drying and solution evaporation, wherein the melt extrusion process comprises the steps of a) preparing a homogeneous melt of each drug; water insoluble polymer and excipients; (b) cooling the melt obtained in step (a); (c) allowing the cooled melt to solidify to obtain extrudates; and (d) processing the extrudates into a desired shape.

WO 2008/029417 discloses a formulation prepared by a process devoid of hot melt extrusion, comprising the steps of: a) mixing at least one antiretroviral drug with at least one pharmaceutical additive in an organic solvent; b) drying said mixture; c) milling said mixture to form milled product; d) compressing said milled product into tablets or filling said milled product into capsules.

WO 2008/067164 discloses a dosage form comprising solid dispersion or solid solution of ritonavir in a matrix of water soluble polymer and surfactant and further discloses a melt extrusion process comprising the steps of (a) preparing a mixture of ritonavir or a combination of ritonavir and another therapeutic agent(s), water soluble polymer and surfactant (b) feeding the mixture in a twin screw extruder to form a homogenous melt and (c) finally compressing the dried melt to form a tablet. The above prior art references disclose various formulations and its preparation for solid oral dosage form comprising lopinavir and ritonavir.

However, still there is a need to develop a process for solid oral dosage form comprising lopinavir and ritonavir, wherein the drug is uniformly distributed. The inventors of the present invention during their continuous effort to produce bioequivalent solid oral dosage form comprising lopinavir and ritonavir developed a process, which involves spraying of one of the melted excipients on the drugs followed by hot melt extrusion technology to maintain an uniform distribution of excipients and the drug. Objective of the invention

Accordingly, the main objective of the present invention is to provide a solid oral dosage form comprising lopinavir and ritonavir prepared by an improved process.

Yet another objective of the present invention is to provide a solid oral dosage form comprising lopinavir and ritonavir prepared by an improved process in such a way that it will comply with the reference product in terms of in vivo parameters like bioequivalence such as C_max, AUC, T_max and in vitro parameters like tablet erosion pattern in dissolution media, disintegration time and dissolution etc. Summary of the invention

Accordingly, the present invention provides a solid oral dosage form comprising lopinavir, ritonavir, water soluble polymer and surfactant prepared by a process comprising the steps of: a) blending lopinavir, ritonavir and one or more excipients, b) heating a surfactant to about 50-80⁰C to form a clear transparent solution, c) spraying the surfactant solution of step (b) on the blend of step (a), d) blending the material of step (c) with water soluble polymer and e) processing the blend of step (d) into a solid dosage form. Detailed description of the invention

In an embodiment of the present invention, the surfactant is heated to about 50-80⁰C and the resulting solution is sprayed on to the blend of lopinavir and ritonavir, which results in uniform mixing of the surfactant with lopinavir and ritonavir blend.

In another embodiment of the present invention, the blend obtained in step (d) is further processed into a solid dosage form using processes selected from melt extrusion, melt granulation, wet granulation, dry granulation, direct compression and solvent evaporation, preferably using melt extrusion process. The melt extrusion process involves preparation of extrudates and is carried out in hot melt extrusion equipment. Various parameters of the hot melt extruder are feed rate, screw speed, zone temperatures, die temperature, melt temperature, chiller temperature and chill roll speed in order to achieve the end product in the form of a solid dispersion with all desirable dosage form and stability characteristics.

The processing conditions involved in making the extrudates, help in uniform distribution of the drugs throughout the blend and also improve the bioavailability.

During the operating process of melt extruder, the setting of zone temperature plays an important role as it affects the product stability and dissolution. An improper setting of zone temperature has certain disadvantages such as:

1. Setting of high temperatures in the starting zones will lead to partial melting of the active blend that will lead to the formation of hard lumps. 2. Improper melting of the active blend due to low temperature in the hot melt extruder, will lead to extrudes with unmelted drugs. 3. Setting of high temperatures in the zones will lead to the decomposition of drugs. The zone temperature of the melt extruder is preset to a gradual increase in temperature ranging from about I⁰C to about 13O⁰C. Most preferably, the melting occurs at the temperature ranging from about 115⁰C to 125⁰C.

The proper distribution of excipients in the formulation is the most important factor as it ultimately affects the bioavailability. As most of the surfactants have low pourability due to viscous nature, it is difficult to properly mix with other excipients and the drug. Moreover, they may form small lumps due to uneven distribution. However, their pourability increases when melted, which can be easily sprayed, to form homogeneous blend. This process also helps in maintaining less temperature in the extruder, which ultimately helps in reduction of hard lumps and also prevents the drug from decomposition.

In another embodiment, the solid oral dosage form of the present invention comprising lopinavir and ritonavir may be in the form of tablet, capsule, powder, dispersible granules or cachet. In another embodiment, the prepared extrudates were further mixed with excipients and compressed into tablets or filled into capsules.

Suitable surfactants according to the present invention are selected from the group comprising polyoxyethylene alkylaryl ethers such as polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether; polyethylene glycol fatty acid esters such as PEG monolaurate, PEG dilaurate, PEG distearate, PEG dioleate; polyoxyethylene sorbitan fatty acid ester such as polysorbate 40, polysorbate 60, polysorbate 80; sorbitan fatty acid mono esters such as sorbitan monolaurate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, polyoxyethylene castor oil derivates such as polyoxyl castor oil, polyoxyl hydrogenated castor oil, copolymers of polyoxyethylene and polyoxypropylene such as poloxamer and the like or combinations thereof. The amount of surfactant used is in the range of about 2 to 20% by weight of the composition.

The pharmaceutically acceptable water soluble polymers according to the present invention include photopolymers and copolymers of N- vinyl lactase, especially photopolymers and copolymers of N-vinyl pyrrolidone, e.g. polyvinylpyrrolidone, copolymers of N-vinyl pyrrolidone and vinyl acetate e.g. copovidone, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, cellulose phthalates or succinates, cellulose acetate phthalate hydroxypropyl methylcellulose phthalate, polyethylene oxide, polyacrylates, methyl methacrylate, butyl methacrylate and the like or combinations thereof. The amount of water soluble polymer used is in the range of about 40 to 80% by weight of the composition.

Yet in another embodiment, the excipients comprise one or more diluents, surfactants, flow regulators, lubricants and the like.

Suitable diluents used according to the present invention are selected from lactose, sucrose, dextrose, mannitol, sorbitol, starch and the like or combinations thereof.

Suitable flow regulators include highly dispersed silica or colloidal silicon dioxide, talc and the like.

Suitable lubricants used according to the present invention are selected from magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, fumaric acid and the like or combinations thereof.

The tablets may be uncoated or optionally coated with film coating composition. If desired, the film coat may be an aqueous moisture barrier. The coating solution mainly comprises of film forming polymers and one or more of plasticizers, opacifier, surfactant, anti tacking agents, coloring agent and the like.

The coating according to the present invention is applied by solubilising or suspending the excipients in solvents such as isopropyl alcohol, water, acetone, ethanol, methylenechloride and the like or mixtures thereof.

In a preferred embodiment, the present invention provides a solid oral dosage form comprising lopinavir, ritonavir, water soluble polymer and surfactant prepared by a process comprising the steps of: a) blending lopinavir, ritonavir and one or more excipients, b) heating about 2 to 20 % w/w of surfactant to about 50-80⁰C to form a clear transparent solution, c) spraying the surfactant solution of step (b) on the blend of step (a), d) blending the material of step (c) with 40 to 80% w/w of water soluble polymer, and e) processing the blend of step (d) into a solid dosage form.

In another preferred embodiment, the present invention provides a solid oral dosage form comprising lopinavir, ritonavir, water soluble polymer and surfactant prepared by a process comprising the steps of: a) blending lopinavir, ritonavir and one or more excipients such as flow regulators selected from colloidal silicon dioxide or talc, b) heating a surfactant selected from sorbitan monolaurate, polyoxyl hydrogenated castor oil to about 50-80⁰C to form a clear transparent solution, c) spraying the surfactant solution of step (b) on the blend of step (a), d) blending the material of step (c) with water soluble polymer such as polyvinylpyrrolidone, copovidone, methyl cellulose and hydroxypropyl methylcellulose and e) processing the blend of step (d) into a solid dosage form. In another preferred embodiment, the present invention provides a solid oral dosage form comprising lopinavir, ritonavir, water soluble polymer and surfactant prepared by a process comprising the steps of: a) blending lopinavir, ritonavir and one or more excipients, b) heating about 2 to 20 % w/w of surfactant to about 50-80⁰C to form a clear transparent solution, c) spraying the surfactant solution of step (b) on the blend of step (a), d) blending the material of step (c) with 40 to 80% w/w of water soluble polymer, and e) loading the blend of step (d) to hot melt extruder and maintaining a gradual increase in zone temperature ranging from about I⁰C to about 13O⁰C to get extrudates, f) milling the extrudates obtained in step (e), g) blending the extrudates of step (f) with one or more excipients and h) compressing the lubricated blend of step (g) into tablets or filled into capsule.

In another preferred embodiment, the present invention provides a solid oral dosage form comprising lopinavir, ritonavir, water soluble polymer and surfactant prepared by a process comprising the steps of: a) blending lopinavir, ritonavir and one or more excipients such as flow regulators selected from colloidal silicon dioxide or talc, b) heating a surfactant selected from sorbitan monolaurate, polyoxyl hydrogenated castor oil to about 50-80⁰C to form a clear transparent solution, c) spraying the surfactant solution of step (b) on the blend of step (a), d) blending the material of step (c) with water soluble polymer such as polyvinylpyrrolidone, copovidone, methyl cellulose and hydroxypropyl methylcellulose, e) loading the blend of step (d) to hot melt extruder and maintaining a gradual increase in zone temperature ranging from about I⁰C to about 13O⁰C to get extrudates, f) milling the extrudates obtained in step (e), g) blending the extrudates of step (f) with one or more excipients such as flow regulators selected from colloidal silicon dioxide, talc; lubricants selected from magnesium stearate, calcium stearate, stearic acid and surfactants selected from polyoxyethylene lauryl ether, polysorbate 40, polysorbate 60, polysorbate 80; sorbitan monolaurate, polyoxyl hydrogenated castor oil, poloxamer and h) compressing the lubricated blend of step (g) into tablets or filled into capsule.

Yet in another embodiment, lopinavir and ritonavir are present in the ratio from about 8:1 to about 3:1.

In another embodiment, the dosage form comprising lopinavir and ritonavir prepared according to the present invention is used for the treatment of HIV infection in an infected individual.

The following examples further exemplify the invention and are not intended to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry. Example 1

The processing steps involved in manufacturing solid dosage form comprising lopinavir and ritonavir are given below: i) lopinavir, ritonavir and colloidal silicon dioxide were sifted and blended using rapid mixer granulator, ii) sorbitan monolaurate was heated to about 60-70⁰C to form a clear transparent solution, iii) the solution of step (ii) was sprayed on to the blend of step (i) by means of spray gun under air pressure, iv) copovidone was mixed with the product obtained in step (iii) using rapid mixer granulator, v) the material obtained in step (iv) was loaded to a hot melt extruder to get extrudates, vi) the extrudates of step (v) was milled and blended with the extragranular colloidal silicon dioxide and sodium stearyl fumarate, vii) compressed the blend of step (vi) to form tablet, viii) prepared the film coating solution and coated tablets to obtain film-coated tablets.

The compositions given in examples 2 to 8 were prepared using similar procedure described in example 1.

Example 2

Example 3

Example 4

Example 5

Example 6

Example 7

Example 8

Dissolution profile of lopinavir and ritonavir tablets prepared according to the present invention was carried out in water with 0.06M polyoxyethylene 10 lauryl ether as dissolution medium using USP Apparatus II with 900 ml at 75 rpm speed. The release profile (% drug released in min) is given in Table 1.

Table 1

The tablets of lopinavir and ritonavir prepared according to example 2 of the present invention were found to be stable. The stability data obtained after 3 months at 4O⁰C/ 75% RH is shown in Table 2.

Table 2

Claims

We claim:

1. A solid oral dosage form comprising lopinavir, ritonavir, water soluble polymer and surfactant prepared by a process comprising the steps of: a) blending lopinavir, ritonavir and one or more excipients, b) heating a surfactant to about 50-80⁰C to form a clear transparent solution, c) spraying the surfactant solution of step (b) on the blend of step (a), d) blending the material of step (c) with water soluble polymer, and e) processing the blend of step (d) into a solid dosage form.

2. The process as claimed in claim 1, wherein the blend of step (d) is further processed into solid dosage form using a process selected from melt extrusion, melt granulation, wet granulation, dry granulation, direct compression or solvent evaporation.

3. The process as claimed in claim 1, wherein the surfactant is selected from the group comprising polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether; PEG monolaurate, PEG dilaurate, PEG distearate, PEG dioleate; polysorbate 40, polysorbate 60, polysorbate 80; sorbitan monolaurate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, polyoxyl castor oil, polyoxyl hydrogenated castor oil, poloxamer and combination thereof.

4. The process as claimed in claim 1, wherein the water soluble polymer is selected from polyvinylpyrrolidone, copovidone, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, cellulose phthalates or succinates, cellulose acetate phthalate hydroxypropyl methylcellulose phthalate, polyethylene oxide, polyacrylates, methyl methacrylate, butyl methacrylate and combination thereof.

5. The process as claimed in claim 1, wherein the excipients comprises one or more diluents, surfactants, flow regulators and lubricants.

6. The process as claimed in claim 5, wherein the flow regulator is selected from highly dispersed silica or colloidal silicon dioxide and talc.

7. The process as claimed in claim 1, wherein the lopinavir and ritonavir are present in the ratio from about 8: 1 to about 3:1.

8. A solid oral dosage form comprising lopinavir, ritonavir, water soluble polymer and surfactant prepared by a process comprising the steps of: a) blending lopinavir, ritonavir and one or more excipients, b) heating about 2 to 20 % w/w of surfactant to about 50-80⁰C to form a clear transparent solution, c) spraying the surfactant solution of step (b) on the blend of step (a), d) blending the material of step (c) with 40 to 80% w/w of water soluble polymer, and e) processing the blend of step (d) into a solid dosage form.

9. A solid oral dosage form comprising lopinavir, ritonavir, water soluble polymer and surfactant prepared by a process comprising the steps of: a) blending lopinavir, ritonavir and one or more excipients such as flow regulators selected from colloidal silicon dioxide or talc, b) heating a surfactant selected from sorbitan monolaurate, polyoxyl hydrogenated castor oil to about 50-80⁰C to form a clear transparent solution, c) spraying the surfactant solution of step (b) on the blend of step (a), d) blending the material of step (c) with water soluble polymer selected from polyvinylpyrrolidone, copovidone, methyl cellulose and hydroxypropyl methylcellulose and e) processing the blend of step (d) into a solid dosage form.

10. An improved process for the preparation of solid oral dosage forms comprising lopinavir and ritonavir, which comprises the steps of: a) blending lopinavir, ritonavir and one or more excipients such as flow regulators selected from colloidal silicon dioxide or talc, b) heating a surfactant selected from sorbitan monolaurate, polyoxyl hydrogenated castor oil to about 50-80⁰C to form a clear transparent solution, c) spraying the surfactant solution of step (b) on the blend of step (a), d) blending the material of step (c) with water soluble polymer selected from polyvinylpyrrolidone, copovidone, methyl cellulose and hydroxypropyl methylcellulose, e) loading the blend of step (d) to hot melt extruder and maintaining a gradual increase in zone temperature ranging from about I⁰C to about 13O⁰C to get extrudates, f) milling the extrudates obtained in step (e), g) blending the extrudates of step (f) with one or more excipients such as flow regulators selected from colloidal silicon dioxide, talc; lubricants selected from magnesium stearate, calcium stearate, stearic acid and surfactants selected from polyoxyethylene lauryl ether, polysorbate 40, polysorbate 60, polysorbate 80; sorbitan monolaurate, polyoxyl hydrogenated castor oil, poloxamer and h) compressing the lubricated blend of step (g) into tablets or filled into capsule.