Pharmaceutical composition for treatment of HIV infection

Abstract

The invention is a pharmaceutical composition for the treatment of HIV infection; containing at least one HIV protease inhibitor as an active ingredient, as well as pharmaceutically acceptable excipients with a specific quantitative component ratio. Additionally, the invention belongs to the process of its production and to a treatment method. The inventive pharmaceutical composition has increased bioavailability and improved technological properties, such as durability, plasticity, disintegration, compared to the prototype drug.

Claims

1. A pharmaceutical composition comprising: at least one HIV protease inhibitor in a therapeutic amount, selected from the group consisting of ritonavir, and lopinavir; a plurality of pharmaceutically acceptable excipients, comprising: at least one water-soluble polymer in an amount of 0.4-20% w/w of a total dosage form; wherein the at least one water-soluble polymer is water-soluble at 20 C.; at least one water-insoluble polymer in an amount of 0.39-28% w/w of the total dosage form; wherein the at least one water-insoluble polymer is water-insoluble at 20 C.; at least two surfactants, wherein the at least two surfactants includes at least one of polysorbate 80 and macrogol 6000; and at least two fillers, wherein when the fillers comprise water-soluble and/or water-insoluble polymers the amount of the at least one water-soluble polymer and the amount of the at least one water-insoluble polymer include the fillers correspondingly; wherein the plurality of pharmaceutically acceptable excipients and the at least one HIV protease inhibitor comprise up to 100% w/w of the total dosage form; wherein the at least one HIV protease inhibitor and the at least one water-insoluble polymer are in a ratio of between 2.5:1 to 120:1; and wherein lower concentrations of the water-soluble polymers by weight increases bioavailability in comparison to similar compositions with higher concentrations by weight of the water-soluble polymers.

2. The pharmaceutical composition according to claim 1, wherein the at least one water-soluble polymer is copovidone.

3. The pharmaceutical composition according to claim 1, wherein the at least one water-soluble polymer is sodium starch glycolate.

4. The pharmaceutical composition according to claim 1, wherein the at least one water-soluble polymer is croscarmellose sodium, homopolymers and copolymers of N-vinyl lactams, polyethylene oxide, polypropylene oxide, copolymers of ethylene oxide and propylene oxide, polyacrylates, polymethacrylates, polyacrylamides, vinyl acetate polymers, polyvinyl alcohol, carrageenans, cellulose esters, cellulose ethers, cellulose succinates, or combinations thereof.

5. The pharmaceutical composition according to claim 1, wherein the at least one water-insoluble polymer is microcrystalline cellulose.

6. The pharmaceutical composition according to claim 1, wherein the at least one water-insoluble polymer is low-substituted hydroxypropyl cellulose.

7. The pharmaceutical composition according to claim 1, wherein the at least two surfactants are in an amount between 0.3-1.0% w/w.

8. The pharmaceutical composition according to claim 1, wherein the at least two fillers are in an amount between 0.3-56% w/w.

9. The pharmaceutical composition according to claim 8, wherein the at least two fillers comprise lactose, modified lactose, sucrose, glucose, mannitol, modified mannitol, sorbitol, fructose, cellulose, cellulose derivatives, starch, modified starch, dextrin, dextrose, dextrate, maltodextrine, calcium, calcium phosphate salt, calcium carbonate salt, calcium chloride salt, magnesium, magnesium oxide, magnesium carbonate, magnesium stearate, crospovidone, cyclodextrines, alginic acid, alginic acid salt, saccharine, saccharine salt, sodium chloride salt, sodium citrate salt, sodium fumarate salt, sodium carbonate salt, aspartame, lactic acid, lactic acid salt, succinic acid, ascorbic acid, tartaric acid, colloidal silicon dioxide, cyclamate, benzoic acid, benzoic acid salts, parabens, parabens salts, or combinations thereof.

10. A pharmaceutical composition comprising: at least one HIV protease inhibitor in a therapeutic amount, selected from the group consisting of ritonavir, and lopinavir; a plurality of pharmaceutically acceptable excipients, comprising: at least one water-insoluble polymer in an amount of 0.39-28% w/w of a total dosage form; wherein the at least one water-insoluble polymer is water-insoluble at 20 C.; at least two surfactants, wherein the at least two surfactants includes at least one of polysorbate 80 and macrogol 6000; and at least two fillers, wherein when the fillers comprise water-soluble and/or water-insoluble polymers the amount of the at least one water-soluble polymer and the amount of the at least one water-insoluble polymer include the fillers correspondingly; wherein the plurality of pharmaceutically acceptable excipients and the at least one HIV protease inhibitor comprise up to 100% w/w of the total dosage form, wherein water-soluble polymers are absent from the composition; wherein the water-soluble polymers are water-soluble at 20 C.; wherein the at least one HIV protease inhibitor and the at least one water-insoluble polymer are in a ratio of between 2.5:1 to 120:1; and wherein absence of the water-soluble polymers increases bioavailability in comparison to compositions with higher concentrations by weight of the water-soluble polymers.

11. The pharmaceutical composition according to claim 10, wherein the at least one water-insoluble polymer is microcrystalline cellulose.

12. The pharmaceutical composition according to claim 10, wherein the at least one water-insoluble polymer is low-substituted hydroxypropyl cellulose.

13. The pharmaceutical composition according to claim 10, wherein the at least two surfactants are in an amount between 0.3-1.0% w/w.

14. The pharmaceutical composition according to claim 10, wherein the at least two fillers are in an amount between 0.3-56% w/w.

15. The pharmaceutical composition according to claim 10, wherein the at least two fillers comprise lactose, modified lactose, sucrose, glucose, mannitol, modified mannitol, sorbitol, fructose, cellulose, cellulose derivatives, starch, modified starch, dextrin, dextrose, dextrate, maltodextrine, calcium, calcium phosphate salt, calcium carbonate salt, calcium chloride salt, magnesium, magnesium oxide, magnesium carbonate, magnesium stearate, crospovidone, cyclodextrines, alginic acid, alginic acid salt, saccharine, saccharine salt, sodium chloride salt, sodium citrate salt, sodium fumarate salt, sodium carbonate salt, aspartame, lactic acid, lactic acid salt, succinic acid, ascorbic acid, tartaric acid, colloidal silicon dioxide, cyclamate, benzoic acid, benzoic acid salts, parabens, parabens salts, or combinations thereof.

16. A pharmaceutical composition comprising: at least one HIV protease inhibitor in a therapeutic amount, selected from the group consisting of ritonavir, and lopinavir; a plurality of pharmaceutically acceptable excipients, comprising: at least one water-soluble polymer in an amount of 0.4-20% w/w of a total dosage form; wherein the at least one water-soluble polymer is water-soluble at 20 C.; at least one water-insoluble polymer in an amount of 0.39-28% w/w of the total dosage form; wherein the at least one water-insoluble polymer is water-insoluble at 20 C.; at least two surfactants, wherein the at least two surfactants includes at least one of polysorbate 80 and macrogol 6000; and at least two fillers, wherein the fillers are selected from the group consisting of lactose, sucrose, glucose, mannitol, sorbitol, fructose, cellulose, cellulose derivatives, starch, dextrin, dextrose, dextrate, maltodextrine, calcium and its salts (phosphates, carbonates, chlorides), magnesium and its derivatives (oxide, carbonate, stearate), cyclodextrines, alginic acid and its salts, saccharine and its salts, sodium salts (chloride, citrate, fumarate, carbonate), aspartame, lactic acid ant its salts, succinic acid, ascorbic acid, tartaric acid, colloidal silicon dioxide, cyclamate, benzoic acid and its salts, and parabens and its salts; wherein the plurality of pharmaceutically acceptable excipients and the at least one HIV protease inhibitor comprise up to 100% w/w of the total dosage form; wherein the at least one HIV protease inhibitor and the at least one water-insoluble polymer are in a ratio of between 2.5:1 to 120:1; and wherein lower concentrations of the water-soluble polymers by weight increases bioavailability in comparison to similar compositions with higher concentrations by weight of the water-soluble polymers.

17. A pharmaceutical composition comprising: at least one HIV protease inhibitor in a therapeutic amount, selected from the group consisting of ritonavir, and lopinavir; a plurality of pharmaceutically acceptable excipients, comprising: at least one water-insoluble polymer in an amount of 0.39-28% w/w of a total dosage form; wherein the at least one water-insoluble polymer is water-insoluble at 20 C.; at least two surfactants, wherein the at least two surfactants includes at least one of polysorbate 80 and macrogol 6000; and at least two fillers, wherein the fillers are selected from the group consisting of lactose, sucrose, glucose, mannitol, sorbitol, fructose, cellulose, cellulose derivatives, starch, dextrin, dextrose, dextrate, maltodextrine, calcium and its salts (phosphates, carbonates, chlorides), magnesium and its derivatives (oxide, carbonate, stearate), cyclodextrines, alginic acid and its salts, saccharine and its salts, sodium salts (chloride, citrate, fumarate, carbonate), aspartame, lactic acid ant its salts, succinic acid, ascorbic acid, tartaric acid, colloidal silicon dioxide, cyclamate, benzoic acid and its salts, and parabens and its salts; wherein the plurality of pharmaceutically acceptable excipients and the at least one HIV protease inhibitor comprise up to 100% w/w of the total dosage form, wherein water-soluble polymers are absent from the composition; wherein the water-soluble polymers are water-soluble at 20 C.; wherein the at least one HIV protease inhibitor and the at least one water-insoluble polymer are in a ratio of between 2.5:1 to 120:1; and wherein absence of the water-soluble polymers increases bioavailability in comparison to compositions with higher concentrations by weight of the water-soluble polymers.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) For a fuller understanding of the invention, reference should be made to the following detailed description, taken in connection with the accompanying drawings, in which:

(2) The FIGURE is a graph showing the mean lopinavir dissolution profile in drugs Kalidavir and Kaletra.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

(3) The set goal is achieved by the fact that the inventors of the said invention developed pharmaceutical composition variations for the treatment of HIV infection that include at least one HIV protease inhibitor and pharmaceutically acceptable excipients with a specific quantitative component ratio.

(4) Based on experimental trials, the authors of the said invention were able to significantly lower the content of water-soluble polymer in the pharmaceutical composition. Upon that it was unexpectedly discovered that dissolution kinetics and biological availability of the claimed pharmaceutical composition has improved significantly as compared to the prototype drug. Thus, the pharmaceutical composition of the described invention decreases the time until therapeutic effect is achieved and is produced through careful selection of qualitative composition and quantitative ratio of excipients.

(5) The authors of the said invention have currently not been able to fully understand the reason behind the improvement of pharmacokinetic properties and the increase of bioavailability following the decrease of water-soluble polymers content in the finished dosage from.

(6) The authors do not exclude the possible effect that water-soluble polymers and surfactants and their interactions have on the described improvements.

(7) Upon creating several variations of the claimed pharmaceutical composition, it was discovered that the reported technical result is achieved, if in one of these variations (further, variation 1 of the pharmaceutical composition) the claimed pharmaceutical composition contains from 0.4 to 49% w/w (in terms of 100% w/w of the total solid dosage form) of water-soluble polymers, and if it also contains from 0.39 to 28% w/w of at least one water-insoluble polymer (of the total finished dosage form). Based on the conducted experimental trials it was discovered that with another content of water-soluble and insoluble polymers the produced finished dosage form has different (decreased as compared to the prototype) properties.

(8) Additionally, the authors have discovered, that the technical result of the claimed invention is also achieved, if the composition in another variation (further, variation 2 of the pharmaceutical composition) of the said invention contains at least one pharmaceutically acceptable water-insoluble polymers in the amount from 0.39 to 28% w/w of the total finished dosage form, surfactants, fillers to 100% of the total finished dosage form, given that water-soluble polymers are not present.

(9) As a result of experimental development of possible finished dosage forms it was discovered that the active substances, which can comprise the claimed pharmaceutical composition, may include nelfinavir, saquinavir, tipranavir, darunavir, indinavir, ritonavir, lopinavir, palinavir, fosamprenavir or their combinations with one another, are also known in the field and are used to treat HIV infection.

(10) In accordance with the invention, the provided drug contains between 5.0% w/w and 60.5% of the active substance (of the total dosage form), as well as pharmaceutically acceptable excipients in the amount from 39.5% to 95.0% of the active substance weight.

(11) Effective amount of the active HIV protease inhibitor substance in dosage form is between 5 mg and 1500 mg.

(12) The claimed antiviral pharmaceutical composition should also preferably contain at least one additional antiviral substance (HIV protease inhibitor) for achievement of synergetic action. HIV protease inhibitors, which could comprise the pharmaceutical composition according to the said invention, may include nelfinavir, saquinavir, tipranavir, darunavir, indinavir, ritonavir, lopinavir, palinavir, or fosamprenavir.

(13) Together with the active substance, the pharmaceutical composition may also contain regular excipients that are acceptable in the process of drug manufacturing, such as binders, fillers, preservatives, flow control agents, softeners, wetting agents, dispersing agents, emulsifiers, solvent, antioxidants and/or propellants, drug carriers. Sucker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgard, 1991.

(14) Pharmaceutical compositions may contain one or more of the following substances as fillers: sugars and their derivatives (lactose, modified lactose, sucrose, glucose, mannitol, modified mannitol, fructose), polysaccharides (cellulose and its derivatives, starch, modified starch), dextrin, dextrose, dextrate, maltodextrin, calcium and its salts, (phosphates, carbonates, chlorides), magnesium and its derivatives (oxide, carbonate, stearate), crospovidone, copovidone, cyclodextrines, alginic acid and its salts, saccharine and its salts, sodium and its salts (chloride, citrate, fumarate, carbonate), aspartame, lactic acid and its salts, succinic acid, ascorbic acid, tartaric acid, colloidal silicon dioxide, cyclamate, benzoic acid and its salts, parabens and their salts.

(15) Pharmaceutical composition should preferably contain from 0.3 to 56% w/w of the fillers mentioned above (in terms of 100% w/w of the total solid dosage form).

(16) Water-soluble polymers that are acceptable for use in the pharmaceutical composition of the said invention may include, but are not limited to the following substances: homopolymers and copolymers of N-vinyl lactarns, especially homopolymers and copolymers of N-vinylpyrrolidone, e.g. polyvinylpyyrrolidone (PVP) copolymers of N-vinylpyrrolidone and vinyl acetate or vinyl propionate; high molecular weight polyalkylene oxides, such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide; polyacrylates and polymethacrylates, such as methacrylic acid/ethyl acrylate copolymers, methacrylic acid/methyl methacrylate copolymers, butyl methacrylate/2-(dimethylamino)ethylmethacrylate copolymers, poly(hydroxyalkylacrylates), poly(hydroxyalkylmethacrylates); polyacrylamides; vinyl acetate polymers, such as copolymers of vinyl acetate and crotonic acid; polyvinyl alcohol; oligo- and polysaccharides, such as carrageenans; cellulose esters and cellulose ethers, in particular methylcellulose and ethyl cellulose, hydroxyalkyl cellulose, in particular hydroxypropylcellulose, cellulose succinates, in particular hydroxypropylcellulose succinate or hydroxypropylcellulose acetate succinate.

(17) Water-insoluble polymers that may be used in the said invention may include, but are not limited to the following substances: microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cellulose ethers (alkyl cellulose ethers, such as ethyl cellulose, ethyl methylcellulose, ethyl propyl cellulose, isopropyl cellulose, butyl cellulose etc.; aralkyl ethers of cellulose, such as benzyl cellulose etc.; cyanoalkyl ethers of cellulose, such as cyanoethyl cellulose, etc.), cellulose esters (cellulose ethers and organic acids, such as cellulose acetate butyrate, cellulose acetate, cellulose propionate, cellulose butyrate, cellulose acetate propionate, etc.), copolymers of methacrylic acid and acrylic acid, etc.

(18) The pharmaceutical composition should preferably contain from 0.4 to 49% w/w of the water-soluble polymers mentioned above, at least one water-insoluble polymer in the amount from 0.39 to 28% w/w of the total finished dosage form, surfactants, fillers up to 100% w/w of the total finished dosage form.

(19) In one of the variations of the said invention, the pharmaceutical composition contains between 0.4 and 20% w/w of the water-soluble polymers mentioned above (in terms of 100% w/w of the total solid dosage form).

(20) Surfactants that are acceptable for use in the pharmaceutical composition of the said invention may include, but are not limited to the following substances: polysorbate 80 (i.e., TWEEN-80 polysorbate), macrogol 6000 (polyethyleneglycol 6000).

(21) The pharmaceutical composition should preferably contain between 0.3 and 1.0% w/w of surfactants (in terms of 100% w/w of the total solid dosage form).

(22) In one of the variations of the said invention, the pharmaceutical composition contains between 0.3 and 0.9% w/w of surfactants (in terms of 100% w/w of the total solid dosage form).

(23) In one of the variations of the said invention, the pharmaceutical composition preferably contains at least one pharmaceutically acceptable water-insoluble polymer in the amount from 0.39 to 28% w/w of the total finished dosage form, surfactants, fillers up to 100% w/w of the total finished dosage form.

(24) The preferred ratio of water-insoluble polymers to surfactants in the claimed pharmaceutical composition should be between 39 and 93.3.

(25) Preferably, the drug may be formulated as powders, tablets, combined tablets, capsules, drage, film-coated granules, suppositories, powders for suspensions. Dosage forms may be formulated in the traditional way (<<Pharmacevticheskaya technologiya. Technologiya lekarstvennyh form>>, 2.sup.nd edition, Moscow, 2006).

(26) The pharmaceutical composition of the invention may be administered orally. Dosage depends on patient's age, health condition, and weight.

(27) The recommended dosage of the combined lopinavir/ritonavir drug for antiretroviral-nave patients is 400/100 mg twice a day or 800/200 mg once a day.

(28) The recommended dosage of the combined lopinavir/ritonavir drug for non-nave patients is 400/100 mg twice a day. Once-a-day administration for such patients is not recommended.

(29) Effective dosage of an active substance of HIV protease inhibitor nelfinavir in dosage form is 750 mg.

(30) Effective dosage of an active substance of HIV protease inhibitor darunavir in dosage form is 300 mg.

(31) Effective dosage of an active substance of HIV protease inhibitor saquinavir in dosage form is 500 mg.

(32) Effective dosage of an active substance of HIV protease inhibitor indinavir in dosage form is 400 mg.

(33) Effective dosage of an active substance of HIV protease inhibitor tipranavir in dosage form is 500 mg.

(34) Effective dosage of an active substance of HIV protease inhibitor fosamprenavir in dosage form is 1400 mg.

(35) Also in accordance with the said invention, an HIV-infection treatment method is claimed, which includes administration to a mammal in need for such treatment the pharmaceutical composition in accordance with the said invention.

(36) The administration method consists of administering a therapeutic dose of the solid dosage form of the pharmaceutical composition, which contains at least one HIV protease inhibitor in therapeutic amount, selected from the group of nelfinavir, saquinavir, tipranavir, darunavir, indinavir, ritonavir, lopinavir, palinavir, or fosamprenavir and pharmaceutically acceptable excipients; among the pharmaceutically acceptable excipients there should be at least one water-soluble polymer in the amount from 0.4 to 49% w/w of the total finished dosage form, at least one water-insoluble polymer in the amount from 0.39 to 28% w/w of the total finished dosage form, surfactants, fillers up to 100% w/w of the total finished dosage form.

(37) In one of the variations, the administration method consists of administering a therapeutic dose of the solid dosage form of the pharmaceutical composition, which comprises of at least one HIV protease inhibitor in a therapeutic amount, selected from the group of nelfinavir, saquinavir, tipranavir, darunavir, indinavir, ritonavir, lopinavir, palinavir, or fosamprenavir and pharmaceutically acceptable excipients; among the pharmaceutically acceptable excipients there should be at least one water-insoluble polymer in the amount from 0.39 to 28% w/w of the total finished dosage form, surfactants, fillers up to 100% w/w of the total finished dosage form.

(38) The following examples demonstrate (without limiting the scope of claim) the most preferable variations of embodiment of the invention; they also confirm the possibility of obtaining the claimed pharmaceutical composition and achievement of the stated technical results.

Example 1

(39) Description of production technology for film-coated tablets:

(40) Active pharmaceutical substances of the HIV protease inhibitor nelfinavir, saquinavir, tipranavir, darunavir, indinavir, ritonavir, lopinavir, palinavir, or fosamprenavir are separately micronised in the water-alcohol solution of surfactants polysorbate 80 and macrogol 6000 for 10 minutes with subsequent dissolution of the substances in D-Sorbitol and lactose carbohydrate and granulation. The blend is dried in a regular manner, in the fluid bed under the temperature of 60 C. until the moisture content of no more than 2.3% is achieved. It is then mixed and dusted by excipients in the following order until homogeneity is achieved: microcrystalline cellulose, sodium starch glycolate, croscarmellose sodium, copovidone (for example, Kollidon VA 64 Copovidone), low-substituted hydroxypropyl cellulose, colloidal silicon dioxide, sodium stearyl fumarate or magnesium stearate. From the obtained mass tablet-cores are formed and coated with water-soluble film.

Example 2

(41) Description of production technology for film-coated lopinavir 100 mg+ritonavir 25 mg tablets

(42) Active pharmaceutical substances of lopinavir and ritonavir are separately micronised in water-alcohol (2:1) solution of sorbitol and polysorbate with macrogol for 10 minutes. Ritonavir suspension is blended with lactose and microcrystalline cellulose. The obtained granulate is dried in a flash drier under the temperature of 45 C. until moisture content of no more than 2.0% is achieved. Micronised lopinavir is homogenised with of lactose and microcrystalline cellulose, granulated, and flash dried under the temperature of 45 C. until moisture content of no more than 2.0-3.0% is achieved. The dried granulate is graded through a 30 mesh vibroscreen, mixed and dusted with low-substituted hydroxypropyl cellulose, colloidal silicon dioxide, and sodium stearyl fumarate in a conical mixer until homogeneous. Out of the powdered granulate 260 mg core-tablets are formed. The tablets are then coated with film in a coating apparatus through spraying of aqueous dispersion for film coating under the temperature of 50 C. until the tablet weight of 267 mg is achieved.

(43) According to the Example 2 listed above, a pharmaceutical composition, which contained 28% w/w of water-insoluble polymers of the following composition, was obtained (all component ratios are provided in terms of 100% w/w of the total tablet weight), as seen in Table 1.

(44) TABLE-US-00001 TABLE 1 A breakdown of components in a first composition of the present invention. meas. tablet units weight % w/w Core composition lopinavir substance mg 100 37.45 ritonavir substance mg 25.0 9.36 low-substituted hydroxypropylcellulose mg 16.02 6.00 microcrystalline cellulose mg 58.74 22.00 lactose mg 44.53 16.68 sorbitol mg 9.61 3.60 polysorbate 80 mg 1.30 0.49 macrogol 6000 mg 1.30 0.49 colloidal silicon dioxide mg 2.0 0.75 sodium stearyl fumarate mg 1.50 0.56 Total: tablet core mg 260 97.38 Finished film: Adv. prima orange (hypromellose, mg 7 2.62 talc, titanium dioxide, macrogol 6000, iron oxide red, yellow) Total: film-coated tablet mg 267 100

(45) According to the Example 2 listed above, a pharmaceutical composition, which contained 0.39% w/w of water-insoluble polymers of the following composition, was obtained (all component ratios are provided in terms of 100% of the total tablet weight), seen in Table 2.

(46) TABLE-US-00002 TABLE 2 A breakdown of components in a composition of the present invention. meas. tablet units weight % w/w Core composition lopinavir substance mg 100 37.45 ritonavir substance mg 25.0 9.36 low-sub stituted hydroxypropylcellulose mg 1.04 0.39 lactose mg 112.08 41.98 colloidal silicon dioxide mg 7.00 2.62 sorbitol mg 9.61 3.60 macrogol 6000 mg 1.30 0.49 sodium stearyl fumarate mg 2.67 1.00 polysorabte 80 mg 1.30 0.49 Total: tablet core mg 260 97.38 Finished film: Adv. prima orange (hypromellose, mg 7 2.62 talc, titanium dioxide, macrogol 6000, iron oxide red, yellow) Total: film-coated tablet mg 267 100

Example 3

(47) Oral Bioavailability Research Technique

(48) Bioavailability research was conducted on male and female dogs weighing approximately 10 kg. During the course of the study all animals were fed a balanced diet containing 27% fat and given unlimited water. Every dog was given a 100 mcg/kg oral dose of histamine (approximately 30 minutes before study drug administration). Every dog was given oral doses containing 200 mg of lopinavir and 50 mg of ritonavir respectively (variation 1 and 2 of the claimed pharmaceutical composition). Afterwards, approximately 10 ml of water was given. Blood samples were collected from each animal before the dose and 0.25, 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours after dose administration.

(49) Plasma and red cells were separated centrifugally and frozen until analysis (30 C.). HIV protease inhibitors were determined through reversed-phase high-performance liquid chromatography with shortwave UV-detection; following that, plasma samples were subjected to solvent extraction. During the study, the area under the curve (AUC) was calculated by using the trapezoidal rule method. Groups of 11-13 dogs were used for evaluation of each dosage form; the provided values are average for each group. Dose-dependent values of drug AUC in dogs by prototype were 10.22 mcg.Math.h/ml/100 mg for ritonavir and 50.2 mcg.Math.h/ml/100 mg for lopinavir. Dose-dependent values of drug AUC (variation 1 of the claimed pharmaceutical composition) in accordance with the said invention in dogs were 30.36 mcg.Math.h/ml/100 mg for ritonavir and 66.2 mcg.Math.h/ml/100 mg for lopinavir.

(50) Dose-dependent values of drug AUC (variation 2 of pharmaceutical composition) in accordance with the said invention 28.36 mcg.Math.h/ml/100 mg for ritonavir and 64.2 mcg.Math.h/ml/100 mg for lopinavir.

(51) The results of this study have shown that pharmaceutical composition bioavailability in accordance with the said invention was higher as compared to the prototype drug.

Example 4

(52) Comparative study of dissolution kinetics of drugs Kalidavir, film-coated tablets (Lopinavir 100 mg+Ritonavir 25 mg), manufactured at the JSC (Joint-Stock Company) Pharmasyntez, Russia, and Kaletra, film-coated tablets (Lopinavir 200 mg+Ritonavir 50 mg), manufactured at Abbott GmBH and Co.KG, Germany

(53) This study was conducted according to GPA (general pharmacopoeia article) 42-0003-04 Dissolution on a paddle mixer apparatus with rotation speed of 75 rpm under the temperature of 370.5 C. Dissolution medium1% sodium dodecyl sulfate solution. Dissolution medium volume900 ml. Sampling time points: 15 min, 30 min, 60 min, 90 min, 120 min. Quantitative evaluation of the released lopinavir and ritonavir was conducted by HPLC (high-performance liquid chromatography).

(54) Kalidavir and Kaletra dissolution profiles are provided in the Figure.

(55) Average amount of lopinavir released within 15 min out of Kalidavir (manufactured at the JSC Pharmasyntez) was 47.09% (i.e., less than 85%), ritonavir107.27% (more than 85%), out of Kaletra (manufactured at Abbott GmBH) the amount of released lopinavir was 27.03%, ritonavir25.81% (i.e., less than 85%).

(56) Thus, the obtained results show that the pharmaceutical composition in accordance with the said invention has better properties as compared to release profile of the prototype drug, which allows to increase bioavailability of the claimed pharmaceutical composition.

Example 5

(57) According to the methodology, describe in Example 1, the produced pharmaceutical composition in a form of a film-coated tablet (lopinavir+ritonavir 200 mg+50 mg, 100 mg+25 mg) has the following components and ratios, % w/w (all component ratios are given in terms of 100% w/w of the total tablet weight), as seen in Table 3.

(58) TABLE-US-00003 TABLE 3 A breakdown of components in a first composition of the present invention. meas. tablet tablet units weight weight % w/w Core composition lopinavir substance mg 100 200 37.45 ritonavir substance mg 25 50 9.36 low-substituted hydroxy- mg 20 40 7.49 propylcellulose macragol 6000 mg 2.5 5 0.94 lactose mg 70 140 26.22 polysorbate 80 mg 2.5 5 0.94 Copovidone (kollidon BA 64) mg 5.5 11 2.06 sodium starch glycolate mg 15 30 5.62 colloidal silicon dioxide mg 7 14 2.62 croscarmellose sodium mg 10 20 3.74 sodium stearyl fumarate mg 2.5 5 0.94 Total: tablet core mg 260 520 100 Finished film: Adv. prima orange (hypromellose, mg 7 14 2.62 talc, titanium dioxide, macrogol 6000, iron oxide red, yellow) Total: film-coated tablet mg 267 534 100

Example 6

(59) The drug is formulated as 5 mg, 10 mg, 25 mg, 50 mg, 100 mg capsules, as seen in Table 4.

(60) TABLE-US-00004 TABLE 4 A breakdown of components in asecond composition of the present invention, presented in various dosages. composition per capsule: mg (%) ritonavir 10(5) .sup.25(12.5) 50(25) 100(50) 121(60.5) crospovidone 10(5) 10(5) 10(5) 10(5) 10(5) mannitol 20(10) 20(10) 20(10) 20(10) 20(10) lactose 150(75) 135(67.5) 110(55) 60(30) .sup.39(19.5) macrogol 6000 8(4) 8(4) 8(4) 8(4) 8(4) sodium stearyl fumarate 2(1) 2(1) 2(1) 2(1) 2(1) weight of capsule contents 200(100) 200(100) 200(100) 200(100) 200(100) water-soluble polymers 8(4) 8(4) 8(4) 8(4) 8(4) (croscarmellose sodium) water-insoluble 10(5) 10(5) 10(5) 10(5) 10(5) polymers (crospovidone)

(61) The sieved powders of ritonavir in the amount of 50.0 g, crospovidone in the amount of 10.0 g, macrogol 6000 in the amount of 8.0 g are put into a tumble mill and micronised for 30 minutes. Micronised ritonavir blended together with macrogol 6000 and crospovidone is granulated in a fluid bed of 20% solution of lactose and mannitol. The produced granulated powder is dusted with 2.0 g of sodium stearyl fumarate in a conical mixer. Capsules are de-dusted and packed into polymer bottles or one-sided dose trays. 1000 drug capsules with a total content weight of 200.0 g or 0.200 g10% are produced; every capsule contains 0.050 g10% of the active ingredient.

Example 7

(62) Film-coated lopinavir+ritonavir 100 mg+25 g tablets, seen in Table 5.

(63) TABLE-US-00005 TABLE 5 A breakdown of components in a third composition of the present invention. meas. tablet substance name unit weight % w/w lopinavir substance mg 100.000 37.4532 ritonavirsubstance mg 25.000 9.3633 Mannitol mg 4.000 1.4981 Microcrystallinecellulose (MCC) mg 10.000 3.7453 Lactose mg 90.600 33.9326 polysorbate 80 mg 1.540 0.5768 Copovidone mg 1.068 0.4000 colloidal silicon dioxide mg 25.000 9.3633 sodium stearyl fumarate mg 2.792 1.0457 Total: tablet core mg 260.000 97.3783 Total: finished film mg 7.0 2.6217 Total: film-coated tablet mg 267.0 93.6330 water-insoluble polymers: MCC mg 10.0 3.7453 water-soluble polymers: copovidone mg 1.068 0.4000

Example 8

(64) Comparative study of dissolution kinetics of drugs Kalidavir, film-coated tablets (Lopinavir 100 mg+Ritonavir 25 mg), manufactured at the JSC Pharmasyntez, Russia, and a the prototype drugKaletra, film-coated tablets (Lopinavir 200 mg+Ritonavir 50 mg), manufactured at Abbott GmBH and Co.KG, Germany.

(65) Series ZT 300 Erweka dissolution tester was used to determine the tablet dissolution time.

(66) The dissolution time for tablets containing 0.39% w/w of water-insoluble polymers (qualitative and quantitative properties correspond to the properties, described in Example 1) was 15 min.

(67) The dissolution time for tablets containing 28% w/w of water-insoluble polymers (qualitative and quantitative properties correspond to the [properties, described in Example 1) was 10 min.

(68) Dissolution time of prototype tablets was 25 min.

(69) Thus, the obtained results show that the pharmaceutical composition in accordance with the said invention has better dissolution properties as compared to the prototype

Example 9

(70) Study of influence of water-soluble and insoluble polymers content on bioavailability.

(71) Non-inbred male rats weighing up to 300-350 g were selected for the oral bioavailability in-vivo study. Rats were kept in vivarium-like conditions with natural light regime and fed a standard laboratory animal diet (GOST P50258-92) in compliance with the International recommendation of the European Convention for the Protection of Vertebrate Animals used for Experimental and Other Scientific Purposes (1997), as well as good laboratory practices of pre-clinical studies in RF. Each rat was prepared by surgical permanent catheter implantation into superior vena cava. The rats were divided into 6 groups of 9. The I group was given an oral dose of the composition containing the following of water-soluble polymers in the amount of 0.4% w/w and water-insoluble polymers in the amount of 0.39% w/w, seen in Table 6.

(72) TABLE-US-00006 TABLE 6 A breakdown of components in a fourth composition of the present invention. Core composition: mg % w/w lopinavir substance 100 37.45 ritonavir substance 25 9.36 low-substituted hydroxypropyl cellulose 1.04 0.39 copovidone 1.068 0.40 Lactose 112.08 41.98 colloidal silicon dioxide 7 2.62 Carbitol 8.542 3.2 macrogol 6000 1.3 0.49 sodium stearyl fumarate 2.67 1 polysorbate 80(tween 80) 1.3 0.49 tablet core weight 260 97.38 finished film weight 7 2.62 film-coated tablet weight 267 100

(73) Water-insoluble polymers 0.39% w/w (1.04 mg), water-soluble polymers 0.4% w/w (1.068 mg).

(74) The II group was given an oral dose of the composition containing the following of water-soluble polymers in the amount of 49% and water-insoluble polymers in the amount of 28% w/w, seen in Table 7.

(75) TABLE-US-00007 TABLE 7 A breakdown of components in a fifth composition of the present invention. mg % w/w Core composition Ritonavir substance 6.55 5.00 Low-substituted hydroxypropyl cellulose 6.55 5.00 Microcrystalline cellulose 30.13 23.00 Povidone 64.19 49.00 Sorbitol 1.00 0.76 Colloidal silicon dioxide 2.00 1.53 Lactose 15.3 11.68 Macrogol 6000 (polyethylene glycol) 0.495 0.38 Polysorbate 80 (tween 80) 0.495 0.38 Sodium stearyl fumarate 0.79 0.60 Total: tablet core weight 127.5 97.33 Finished film Film weight 3.5 2.67 Film-coated tablet weight 131 100

(76) Water-soluble polymers (povidone)49% w/w

(77) Water-insoluble polymers (Low-substituted hydroxypropyl cellulose, microcrystallinecellulose)28% w/w

(78) The III group of rats was given an oral dosage of the composition containing 0.39% w/w of water-insoluble polymers (pharmaceutical composition corresponds to the composition, described in Example 2).

(79) The IV group of rats was given an oral dosage of the composition containing 28% w/w of the following water-insoluble polymers, seen in Table 8.

(80) TABLE-US-00008 TABLE 8 A breakdown of components in a sixth composition of the present invention. mg % w/w Core composition Lopinavir substance 100 37.45 Ritonavir substance 25 9.36 Low-substituted hydroxypropyl cellulose 16.02 6.00 Microcrystalline cellulose 58.74 22.00 Lactose 44.53 16.68 Sorbitol 9.61 3.60 Polysorbate 80 (tween 80) 1.30 0.49 Macrogol 6000 1.30 0.49 Colloidal silicon dioxide 2.00 0.75 Sodium stearyl fumarate 1.50 0.56 Total: tablet core weight 260 97.38 Finished film Film weight 7.00 2.62 Film-coated tablet weight 267 100

(81) Water-insoluble polymers (Low-substituted hydroxypropyl cellulose, microcrystalline cellulose)28% w/w.

(82) The IV group of rats was given an oral dosage of the composition containing 0.4% w/w of water-soluble polymers and 3.75% w/w of water-insoluble polymers. The pharmaceutical composition corresponds to the composition, describe in Example 7.

(83) Kaletra tablets were used as comparator, were given orally to group IV (control group) and had the following composition (g), as seen in Table 9.

(84) TABLE-US-00009 TABLE 9 The composition of Kaletra tablets. Active substances: Lopinavir 100 mg, ritonavir 25 mg; Excipients:

(85) Copovidone K 28426.9 mg; sorbitan laurate41.95 mg; colloidal silicon dioxide6.0 mg; second layer: sodium stearyl fumarate6.15 mg; colloidal silicon dioxide4.0 mg; film coating: Opadry II pink 85 F 1439915.0 mg, polyvinilalcohol40.00%, titanium dioxide24.85%, talc14.80%, macrogol 335020.20%, iron oxide red E1720.15%.

(86) Comparator drugs were given once in a dose that nominally corresponds to the of a dose recommended for humans.

(87) Consecutive blood samples of 0.25 ml were collected via the permanent catheter in 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after drug administration. These samples were analysed using an HPLC assay for the tested compounds. Each of the three composition concentrations were plotted against the time after oral administration, and AUC (area under the curve of plasma concentration vs. time) was integrated using trapezoidal method for calculation of absolute bioavailability, reflected in Table 10.

(88) TABLE-US-00010 TABLE 10 The bioavailability of the test compositions in the model study groups. Mean absolute oral Rat study group bioavailability(%) I 86 II 96 III 79 IV 85 V 88 VI(control group) 75

(89) Thus, the results of the conducted studies have unexpectedly shown that the pharmaceutical composition containing 0.4% w/w of water-soluble polymers and 0.39% w/w of water-insoluble polymers allowed for an 11% increase of absolute bioavailability as compared to the prototype. Pharmaceutical composition containing 49% w/w of water-soluble polymers and 28% w/w of water-insoluble polymers allowed for a 21% increase of absolute availability as compared to the prototype. For the pharmaceutical composition containing 0.39% w/w of water-insoluble polymers, the absolute bioavailability was similar to the prototype composition, but was 4% higher. For the pharmaceutical composition containing 28% w/w of water-insoluble polymers, the absolute bioavailability was 10% higher and had a value of 85%.

(90) The authors of the said invention have unexpectedly discovered that the content of water-soluble and insoluble polymers within the claimed compositions has an effect on such technological properties as strength and ductility of the dosage form. The results of the conducted studies have shown that the finished dosage forms (tablets) containing water-soluble polymers in the amount between 0.4 and 49% w/w, as well as water-insoluble polymers in the amount between 0.3 and 28% w/w are stronger compared to the prototype. Additionally, tablets in accordance with the said invention also have higher ductility due to the use of high-ductile polymers, which leads to smaller losses during tabletisation, increases tabletisation speed, and provides for easier swallowing of the tablets.

(91) Mechanical strength of the tablets was measured by tablet friability. The evaluation of tablet friability was conducted on an Agilent Friability Tester. Prototype tablet strength by friability was 98%. Strength of tablets containing 0.4% of water-soluble polymers and 0.39% of water-insoluble polymers was 99.4%. Strength of tablets containing 49% of water-soluble polymers and 28% of water-insoluble polymers was 99.8%. Strength of tablets containing 0.39% of water-insoluble polymers was 99%. Strength of tablets containing 28% of water-insoluble polymers was 99.2%.

(92) Thus, the claimed invention allows to obtain new and more effective (compared to the prototype) pharmaceutical composition with improved technological properties (strength, ductility, disintegration ability), as well as improved dissolution kinetics and increased (compared to the prototype) bioavailability.