FIELD OF INVENTION
The present invention relates to a pharmaceutical formulation and in particular to pharmaceutical compositions for use in HIV therapy. It also discloses the processes to make the same. The invention has been developed primarily for use of the formulation in the treatment of HIV diseases and will be described hereinafter with reference to this application. However, it will be appreciated that the invention is not limited to this particular field of use.
BACKGROUND OF THE INVENTION and related prior art
HIV therapy formulations/compositions need to be made in the most economical manner thereby reducing the final prices for AIDS patients across the world, especially in third world and developing countries. There are niultiple formulations being used in HIV treatment therapy. The active substance Ritonavir [NORVIRTM soft gelatin capsule] is characterized by low aqueous solubility, a lack of bioavailability when given in the solid state, instability once in solution under ambient conditions and a metallic taste.
US5484801 discloses a formulation wherein Ritonavir formulation has been optimized with respect to the vehicle, which essentially is a solvent comprising a mixture of (1) (a) a solvent selected from propylene glycol and polyethylene glycol or (b) a solvent selected from polyoxyethyleneglycerol triricinoleate, polyethylene glycol 40 hydrogenated castor oil, fractionated coconut oil, polyoxyethylene (20) sorbitan monooleate and 2-(2-ethoxyethoxy) ethanol or (c) a mixture thereof and (2) ethanol or propylene glycol to improve the bioavailability.
OBJECTS OF THE INVENTION
It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative.
It is an object of the invention in its preferred form to provide an economical formulation for administration of at least one anti-retro viral drug

selected from the group of protease inhibitors or Nucleoside Reverse Transcriptase Inhibitor or Non-Nucleoside Reverse Transcriptase Inhibitor.

It is an object of the invention in its preferred form to provide an economical formulation for administration of Ritonavir in a stable formulation.
i SUMMARY OF THE INVENTION
According to the invention there is provided a pharmaceutical formulation for use in HIV therapy comprising a solid dispersion of at least one HIV protease inhibitor in at least one pharmaceutically acceptable water-soluble carrier and at
least one pharmaceutically acceptable surfactant. According to one aspect of the
ii
invention there is also provided a process to make the same.
The present invention, in its preferred form, is directed to a solid pharmaceutical dosage form comprising ritonavir and a process for preparing same. The present invention provides a solid pharmaceutical dosage form comprising a solid dispersion of ritonavir, a pharmaceutically acceptable water-soluble carrier and at least one pharmaceutically acceptable surfactant. Optionally, other suitable pharmaceutical excipients may be incoiporated.
DETAILED DESCRIPTION INCLUDING PREFERRED EMBODIMENTS OF THE INVENTION:
The commercially available Ritonavir capsule has an inherent limitation of thermal stability, as the patient information label for NORVIRTM soft gelatin capsules indicates that storage to be done in a refrigerated envirormient. [Store soft gelatin capsules in the refrigerator between 36-46°F (2-8°C) until dispensed].
Therefore, keeping in view of the above limitation of NORVIRTM soft gelatin capsules, a great need of solid oral dosage form with better thermal stability without having any impact on the oral bioavailability was felt. To overcome the problem of thermal stability for the ritonavir formulation, the approach of solid dispersion technique was explored.

"Solid dispersion" defines a system in a solid state (as opposed to a liquid or gaseous state) comprising at least two components, wherein one component is dispersed evenly throughout the other component or components. For example, the active ingredient or combination of active ingredients is dispersed in a matrix comprised of the pharmaceutically acceptable water-soluble non-polymeric excipient(s) and pharmaceutically acceptable surfactant(s). Solid dispersions are preferred physical systems because the components therein readily form liquid solutions when contacted with a liquid medium such as gastric juice. The ease of dissolution may be attributed at least in part to the fact that the energy required for dissolution of the components from a solid solution is less than that required for the dissolution of the components from a crystalline or microcrystalline solid phase.
The term "solid dispersion" encompasses systems having small particles, typically of less than 1 m in diameter, of one phase dispersed in another phase. When said dispersion of the components is such that the system is chemically and physically uniform or homogenous throughout or consists of one phase (as defined in thermodynamics), such a solid dispersion will be called a "solid solution" or a "glassy solution". A glassy solution is a homogeneous, glassy system in which a solute is dissolved in a glassy solvent. Glassy solutions and solid solutions of HIV protease inhibitors are preferred physical systems. These systems do not contain any significant amounts of active ingredients in their crystalline or microcrystalline state, as evidenced by thermal analysis (DSC) or X-ray diffraction analysis.
The term "pharmaceutically acceptable surfactant" as used herein refers to a pharmaceutically acceptable non-ionic surfactant. In one embodiment, the dosage form comprises at least one surfactant having a hydrophilic-lipophilic balance (HLB) value of from about 4 to about 10, preferably from about 7 to about 9. Known surfactants like esters of polyethylene glycols, sucrose fatty acid

esters, e.g. sucrose monostearate, sucrose distearate, sucrose monolaurate, sucrose dilaurate; or sorbitan fatty acid mono esters such as sorbitan mono laurate (Span series) can be effectively employed.
If Besides the surfactant having an HLB value of from about 4 to about 10,
the dosage form may comprise additional pharmaceutic ally acceptable surfactants
such as polyoxyethylene castor oil derivates, e.g. polyoxyethyleneglycerol
triricinoleate or polyoxyl 35 castor oil (Cremophor® series); or block copolymers
of ethylene oxide and propylene oxide, also known as polyoxyethylene
polyoxypropylene block copolymers or polyoxyethylene polypropylene glycol
(Poloxamer® series, from BASF Wyandotte Corp.); or a mono fatty acid ester of
polyoxyethylene (20) |( sorbifan (Tween® series). The sorbhan mono fatty acid
esters are preferred, with sorbitan mono laurate and sorbitan monopalmitate being
particularly preferred.
The pharmaceutically acceptable water soluble carrier used in this
invention can be selected from but are not limited to sugar alcohols, for example
sorbitol, mannitol etc. or organic acids of the likes of citric acid, succinic acid, tartaric acid or polymers such as polyvinyl pyrollidone, cellulose derivatives, gums, and the likes. Although the invention has been described with reference to specific examples, it will be appreciated by those skilled in the art that the invention may be embodied in other forms.
Method of preparation
Various methods can be used for manufacturing the solid dosage forms according to the invention. These methods comprise the preparation of a solid solution of the HIV protease inhibitor or the combination of HIV protease inhibitors in a matrix of the water-soluble carrier and the surfactant, and shaping into the required tablet form. Alternatively, the solid solution product may be

subdivided to granules, e.g. by grinding or milling, and the granules may subsequently be compacted to tablets.
Various techniques exist for preparing solid solutions including melt-extrusion, spray-drying and solution-evaporation. Melt granulation with solvent evaporation or solution'[evaporation being preferred processes.
The melt-extrUsion process comprises the steps of preparing a homogeneous melt of the HIV protease inhibitor or the combination of HIV protease inhibitors, the water-soluble carrier and the surfactant, and cooling the melt until it solidifies. In one instance, the melt-extrusion process comprises the steps of preparing a homogeneous melt of ritonavir, the surfactant and the water-soluble carrier and, and cooling the melt until it solidifies.
"Melting" means a transition into a liquid or rubbery state in which it is possible for one component to get embedded homogeneously in the other. Typically, one component will melt and the other components will dissolve in the melt thus forming a solution. Melting usually involves heating above the softening point of the water-soluble carrier. The preparation of the melt can take place in a variety of ways. The mixing of the components can take place before, during or after the formation of the melt. For example, the components can be mixed first and then melted or be simultaneously mixed and melted. Usually, the melt is homogenized in order to disperse the active ingredients efficiently.
Usually, the melt temperature is in the range of about 70 to about 250°C., preferably from about 80 to about 180°C., most preferred from about 100 to about
140°C. The active ingredients can be employed as such or as a solution or
i
dispersion in a suitable solvent such as alcohols, aliphatic hydrocarbons or esters. Another solvent which can be used is liquid carbon dioxide. The solvent is removed, e.g. evaporated, upon preparation of the melt. Various additives may be included in the melt for example flow regulators such as colloidal silica;

lubricants, fillers, disintegrants, plasticizers, stabilizers such as antioxidants, light stabilizers, radical scavengers, stabilizers against microbial attack.
The melting and/ or mixing takes place in an apparatus customary for this purpose. Particularly suitable ones are extruders or kneaders. Suitable extruders include single screw extruders, intermeshing screw extruders or else multi-screw extruders, preferably twin screw extruders, which can be co-rotating or counter-rotating and, optionally, be equipped with kneading disks. It will be appreciated that the working temperatures will also be determined by the kind of extruder or the kind of configuration within the extruder that is used.
The melt ranges from pasty to viscous. Shaping of the extrudate conveniently is carried;out by a calendar with two counter-rotating rollers with mutually matching depressions on their surface. A broad range of tablet forms can be attained by using rollers with different forms of depressions. Alternatively, the extrudate is cut into pieces, either before (hot-cut) or after solidification (cold-cut).
Optionally, the: resulting solid solution product is milled or ground to granules. The granules may then be compacted. Compression of the powder mass is usually done in a tablet press, more specifically in a steel die between two moving punches. Where a solid dosage form of the invention comprises a combinafion of more than one HIV protease inhibitor (or a combination of an HIV protease inhibitor with one or more other active ingredients) it is of course possible to separately prepare solid solution products of the individual active ingredients and to blend the milled or ground products before compacting.
Apart from the 'active premix or solid solution or solid dispersion, other conventional excipients like flow regulators, disintegrants, bulking agents, lubricants etc., can be used to compress tablets.

Dosage forms according to the invention may be provided as dosage forms consisting of several layers, for example laminated or multilayer tablets. They can be in open or closed form. "Closed dosage forms" are those in which one layer is completely surrounded by at least one other layer. Multilayer forms have the advantage that two active ingredients which are incompatible with one another can be processed, or that the release characteristics of the active ingredient(s) can be controlled. For example, it is possible to provide an initial dose by including an active ingredient in one of the outer layers, and a maintenance dose by including the active ingredient in the inner layer(s).
Multilayer tablets types may be produced by compressing two or more layers of granules. Alternatively, multilayer dosage forms may be produced by a process known as "co-extrusion". In essence, the process comprises preparation of at least two different rnelt compositions as explained above, and passing these molten compositions into a joint co-extrusion die. The shape of the co-extrusion die depends on the required drug form. For example, dies with a plain die gap, called slot dies, and dies with an annular slit are suitable.
Optionally, the compressed tablets can be film-coated. A film coat on the tablet further contributes to the ease with which it can be swallowed. A film coat also improves taste and provides an elegant appearance. If desired, the film-coat may be an enteric coat.
Inline with the disclosed invention, the exemplary compositions are given below to further illustrate the invention without limiting it. These compositions are processed by solvent evaporation technique. The prepared tablets were coated with Opadry aqueous dispersion.


Brief Manufacturing Process:
1. Dissolve Ritonavir in ethanol.
2. Mix well Sorbitol, sorbitan monolaurate and colloidal silicon dioxide and add it to ethanol to prepare dispersion.
3. Add step no 1 solution to step no. 2 dispersion and mix well.
4. Evaporate the solvent of step no 3 to prepare a premix.
5. Mill the premix to obtain a suitable particle size distribution.
6. Sift sodium stearyl fumarate and colloidal silicon dioxide and add to the premix and blend.
7. Compress the blend of step no. 6 to prepare tablets.
8. Coat the tablets of step no. 7.

Brief Manufacturing Process:
1. Mix well citric acid anhydrous, sorbitan monolaurate and colloidal silicon dioxide and add it to Ritonavir and mix well.

2. Heat the mixture of step no. 1 to about 120 - 140°C to get a molten mass
and cool it immediately to obtain a solid mass.
3. Mill the solid mass of step no. 2 to obtain a suitable particle size
distribution.
4. Sift sodium stearyl fumarate and colloidal silicon dioxide and add to the
1. I
premix and blend.
5. Compress the blend of step no. 4 to prepare tablets.
6. Coat the tablets of step no. 5.

Brief Manufacturing Process:
1. Mix well Polyoxyethylene Glycerol Oxystearate, sorbitan monolaurate and
colloidal silicon dioxide and add it to Ritonavir and mix well.
2. Heat the mixture of step no. 1 to about 120 - 140°C to get a molten mass
and cool it immediately to obtain a solid mass.
3. Mill the solid mass of step no. 2 to obtain a suitable particle size
distribution.
4. Sift sodium stearyl fumarate and colloidal silicon dioxide and add to the
premix and blend.
5. Compress the blend of step no. 4 to prepare tablets.
6. Coat the tablets of step no. 5.


Brief Manufacturing Process:
1. Mix well Ritonavir and mannitol.
2. Mix well sorbitan moriolaurate and colloidal silicon dioxide and add it to
dry mix of Ritonavir and mannitol.
3. Dissolve the mixture of step no. 2 in a mixture of water and ethanol.
4. Evaporate the step no. 3 solution to prepare a premix.
5. Mill the premix of step no. 4 to obtain a suitable particle size distribution.
6. Sift sodium stearyl fumarate and colloidal silicon dioxide and add to the premix and blend.
7. Compress the blend of step no. 6 to prepare tablets.
8. Coat the tablets of step no. 7.

■i Brief Manufacturing Process:
1. Mix well tartaric acid, sorbitan monolaurate and colloidal silicon dioxide and add it to Ritonavir and mix well.

2. Heat the mixture jof step no. 1 to about 120 - 140°C to get a molten mass
and cool it immediately to obtain a solid mass.
3. Mill the solid mass of step no. 2 to obtain a suitable particle size
distribution.
4. Sift sodium stearyl fumarate and colloidal silicon dioxide and add to the
premix and blend.
5. Compress the blend of step no. 4 to prepare tablets.
6. Coat the tablets of step no. 5.

I
r
Brief Manufacturing Process:
1. Mix well dextrose, sorbitan monolaurate and colloidal silicon dioxide and
add it to Ritonavir and mix well.
2. Heat the mixture of step no. 1 to about 120 - 140°C to get a molten mass
and cool it immediately to obtain a solid mass.
3. Mill the solid mass of step no. 2 to obtain a suitable particle size
distribution.
4. Sift sodium stearyl fumarate and colloidal silicon dioxide and add to the
premix and blend.
5. Compress the blend of step no. 4 to prepare tablets.
6. Coat the tablets of step no. 5.


Brief Manufacturing Process:
1. Dissolve Ritonavir and Sorbitan monolaurate in Methylene chloride in a
suitable container.
2. Sift Copovidone and Colloidal silicon dioxide through a suitable screen or
sieve (ASTM) and collect in a suitable container.
3. Add the sifted ingredients of step no. 2 to step no. 1 solution under stirring
in suitable equipment.
4. Dry the material of step no. 3 at a suitable temperature under vacuum and
for sufficient period of time.
5. Mill the dried mass and sift through a suitable screen or sieve.
6. Sift Sodium Chloride, Sodium Stearyl Fumarate and Colloidal Silicon
Dioxide through a suitable sieve or screen.
7. Load the sifted material of step no. 5 and step no. 6 in a blender and blend for a suitable period of time
8. Compress the blend of step no. 3 into tablets using suitable tooling.
9. Coat the compressed tablets with aqueous dispersion of Opadry Yellow.

Stability Data:
The composition illustrated in Example 7 was subjected to stress conditions at 40°C/ 75% RH and 30°C/ 75% RH for 3 months and was compared with the NORVIR™ (Batch No. 47833 2 E 22) which was also stressed under the similar conditions.
The following data suggests that the composition of the present invention has a better stability as compared to the commercially available formulation of Ritonavir. After 3 months of storage under the given stress conditions, the degradation of Ritonavir! in the solid dispersion form of the invention, is less as compared to that of NORVIR^'^, which is ftirther, attributed by less reduction in the assay value of the same. Moreover the impurities levels are not substantially increased as compared with NORVIR^'^.
Thus, from above, it is'fapparent that the composition according to the present invention provides more stable formulations of Ritonavir over the commercially available ones.

We claim:
1. A solid pharmaceutical composition for oral administration of HIV protease
inhibitor(s) comprising:
a solid-dispersion of said HIV protease inhibitor(s) with at least one water-soluble carrier
and optionally at least one surface-active agent and other pharmaceutical ly acceptable excipients.
2. The solid pharmaceutical composition according to claim 1, wherein said HIV
protease inhibitor(s) are selected from a group consisting of : ( 2S,3S, 5S)-5-, (N-
(N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinyl)
amino-2-(N-((5-thiazolyl)methoxy-carbonyl)-amino)-amino-l,6-diphenyl-3- '
hydroxy hexane (ritonavir); (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-
hydroxy-5-[2S-(l-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl]amino,l,6-
diphenylhexane (lopinayir); N- (2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4
(S)-hydroxy-5-(l-(4-(3-pyridylmethyl)-2(S)-N'-(t-butylcarboxamido)-
piperazinyl))-pentanearnide (indinavir); N-tert-butyl-decahydro-2-[2(R)-hydroxy-
4-phenyl-3(S)-[pS[-(2-quinolyIcarbonyl)-Lasparaginyl]amino] butyl]-(4aS,8aS)-
isoquinoline-3(S)-carboxamide (saquinavir); 5(S)-Boc-amino-4(S)-hydroxy-6-
phenyl-2(R) phenylmethylhexanoyl- (L)-Val-(L)-Phemorpholin-4-ylamide or
combinations thereof.
3. A process of preparing a solid pharmaceutical composition for oral
administration of HIV protease inhibitor(s) which comprises
(i) preparing a solution or dispersion comprising said HIV protease inhibitor(s),
and a water-soluble carrier and a surfactant(s), in pharmaceutically acceptable
I solvent(s);
(ii) evaporating said solution or dispersion to obtain a solid dispersion product;
(iii) milling/grinding said solid dispersion product to produce granules/particles;
(iv) optionally adding other pharmaceutically acceptable excipients;
(v) compacting said granules/ particles to tablets and

(vi) optionally coating said tablet.
4. The solid pharmaceutical composition according to claim 1 or 3, wherein said water-soluble carrier is' selected from a group consisting of lactose, maltose, dextrose, sucrose, fructose, carbohydrate, alpha-hydroxy acid, marmitol, sorbitol, xylitol, dicalcium phosphate, calcium sulfate, lactitol, glucose, mannitol, citric acid, succinic acid, tartaric acid and derivatives of the foregoing, polyvinyl pyrrolidone derivatives, cellulose derivatives, gums or combinations thereof.
5. The solid pharmaceutical composition according to claim 1 or 3 wherein said pharmaceutically acceptable water-soluble carrier is copovidone.
6. The solid pharmaceutical composition according to claim 1 or 3 wherein said pharmaceutically acceptable surface-active agent is a sorbitan fatty acid ester.
7. A solid pharmaceutical dosage form comprising a solid dispersion of (2S,3S, 5S)-5-(N-(N-((N-methyl-N-((2-isopropyl-4-thiazolyl) methyl) amino) carbonyl)-L-valinyl) amino-2-(N-((5-thiazolyl) methoxy-carbonyl)-amino)-amino-1,6-diphenyl-3-hydroxy hexane (ritonavir), copovidone; a sorbitan fatty acid ester; and optionally other pharmaceutically acceptable excipients.
8. The solid pharmaceutical composition of claim 7 further comprising of at least one additive selected from diluents, bulking agents, disintegrants, flow regulators
and lubricants.
,1
9. A solid pharmaceutical composition comprising:
(i) (2S,3S,5S)-5-(N-(N-((N-methyl-N-((2-isopropyl-4-thiazolyl) methyl) amino)
carbonyl) -L- valinyl) amino-2-(N-((5-thiazoIyl)methoxy-carbonyl)-amino)-
amino-l,6-diphenyl-3-hydroxy hexane (ritonavir);
(ii) copovidone from about 60 % to about 85 % by weight;
(iii) and a sorbitan fatty acid ester from about 5 % to about 10 % by weight

and optionally other pharmaceutically acceptable excipients.
10. A solid pharmaceutical composition for oral administration of HIV protease inhibitor(s) comprising, a solid-dispersion of the drug with: i) at least one water-soluble carrier and/or ii) at least one surface-active agent or a combination of both (i) and (ii) and optionally other pharmaceutically acceptable excipients having an improved stability over the commercially available NORVIR^'^ capsules.