EA040125B1 - PHARMACEUTICAL COMPOSITION WITH ACTIVITY AGAINST HIV INFECTION, INCLUDING LOPINAVIR AND RITONAVIR ON SORBENT - Google Patents

Description

The invention relates to the field of pharmaceutical industry.

HIV protease inhibitors (PIs), which include lopinavir and ritonavir, are substances that have an affinity for the active site of the HIV protease, which should cleave the Gag-Pol virus polyprotein into individual functional proteins. As a result of the action of protease inhibitors, the protease does not perform its function and viral particles are formed that are not able to infect new cells. PIs often have side effects on the gastrointestinal tract. With prolonged use, lipid metabolism disorders of varying severity and the development of lipodystrophy are possible.

Among the HIV protease inhibitors known substances such as nelfinavir, saquinavir, tipranavir, darunavir, indinavir, atazanavir, ritonavir, lopinavir, palinavir, fosamprenavir.

Almost all HIV protease inhibitors are known to belong to the second class of BSCs. In this regard, technological difficulties arise in the process of creating finished dosage forms based on these substances. The main task in creating new finished dosage forms is the selection of technology and composition, so as to improve or freely regulate the kinetics of the release of active substances, stabilize the finished dosage form, simplify the technological scheme, reduce the weight of the finished dosage form, to increase ease of administration.

The prior art drug Kaletra® film-coated tablets (lopinavir 200 mg + ritonavir 50 mg) manufactured by Abbott GmbH and Co. KG, Germany, which is described in patent EA 011924 and taken as a prototype.

As follows from the patent EA 0011924, the authors have made an attempt to improve the bioavailability of the solid dosage form of lopinavir + ritonavir. This problem was solved by introducing into the composition of the finished dosage form water-soluble polymers in a sufficiently large amount from about 50% to about 85 wt.% and a pharmaceutically acceptable surfactant in an amount from about 2% to about 20 wt.% relative to the weight of the dosage form , as well as the use of thermoplastic extrusion technology.

WO 01/00175 discloses mechanically stable pharmaceutical dosage forms which are solid solutions of active ingredients in an adjunct matrix. The matrix contains an N-vinylpyrrolidone homopolymer or copolymer and a liquid or semi-liquid surfactant.

WO 00/57854 discloses mechanically stable pharmaceutical dosage forms for oral administration which contain at least one active compound, at least one thermoplastically moldable matrix excipient, and from more than 10 to 40% by weight of a surfactant which has an HLB value (hydrophilic lipophilic balance index) of 2 to 18, is liquid at 20°C, or has a dropping point of 20 to 50°C.

One of the ways to improve the bioavailability of sparingly soluble substances is technologies that prevent the formation of crystals of these substances, in particular, the immobilization of active substance molecules on the developed surface of sorbents. The obligatory steps of this technology are the dissolution of the active substance, the application of a solution of the active pharmaceutical ingredient and possibly, but not necessarily, additional excipients to the sorbent, and the formation of a mixture for tableting or filling capsules. As a result of carrying out the process according to this technology, a complex is formed from individual molecules of the active substance and sorption centers of the sorbent. Also, a polymer can be added to the solution of the active substance, which additionally prevents the crystallization of the substance and accelerates dissolution. Additionally, solubilizers and disintegrants may be added. There are a number of difficulties in selecting the appropriate composition of excipients and process parameters. There is constant research aimed at developing new compositions suitable for solving the problem.

Brief description of the figures

Fig. 1. Kinetics of lopinavir release from tablet dosage forms. Dissolution medium - 38 g of polyoxyethylene-10-lauryl ether in 1 l of water. On the abscissa axis - the dissolution time in minutes, on the ordinate axis - the percentage of the substance that passed into the solution in percent.

Graph 1 corresponds to example 1, graph 2 corresponds to example 2, graph 3 corresponds to example 3, graph 4 corresponds to example 4, graph 5 corresponds to example 5, graph 6 corresponds to example 6, graph 7 corresponds to example 7, graph 8 corresponds to example 8, graph 9 corresponds to example 9, graph 0 corresponds to the reference drug.

Fig. 2. Release kinetics of ritonavir from tablet dosage forms. Dissolution medium - 38 g of polyoxyethylene-10-lauryl ether in 1 l of water. On the abscissa axis - the time of dissolution in

- 1 040125 minutes, along the y-axis - the percentage of the substance that has passed into solution in percent.

Graph 1 corresponds to example 1, graph 2 corresponds to example 2, graph 3 corresponds to example 3, graph 4 corresponds to example 4, graph 5 corresponds to example 5, graph 6 corresponds to example 6, graph 7 corresponds to example 7, graph 8 corresponds to example 8, graph 9 corresponds to example 9, graph 0 corresponds to the reference drug.

Fig. 3. The plot of the development field demonstrates the dependence of the dissolution kinetics (along the y-axis), where 10 is the optimality,

- the amount of ritonavir passed into solution in 90 minutes,

- the amount of lopinavir that passed into the solution in 90 minutes,

- the amount of ritonavir passed into the solution in 60 minutes,

- the amount of lopinavir that passed into the solution in 60 minutes,

- the amount of ritonavir passed into the solution in 45 minutes,

- the amount of lopinavir that passed into the solution in 45 minutes,

- the amount of ritonavir passed into the solution in 30 minutes,

- the amount of lopinavir that passed into the solution in 30 minutes,

- the amount of ritonavir passed into the solution in 15 minutes,

- the amount of lopinavir that passed into the solution in 15 minutes, from the content of the component (along the x axis), where

- sodium stearyl fumarate,

- colloidal silicon dioxide,

- povidone,

- sodium carboxymethylcellulose,

- sodium starch glycolate,

- sorbitan laurate,

- optimality.

The shaded fields (the most pronounced angle of the black line in relation to the horizontal line) indicate significance (the saturation of the shade indicates the degree of influence of this component on the kinetics of dissolution of the active substances.

Fig. 4. Graph of the development field, where the lightest part of the graph corresponds to such a content of excipients that allows you to achieve an equal release profile of active substances from the drug under development, relative to the reference drug, and where

- sodium stearyl fumarate,

- colloidal silicon dioxide,

- povidone,

- sorbitan laurate.

The objective of the invention is the development of alternative compositions and technologies for the production of the dosage form of the drug (HIV protease inhibitor) and the improvement of the pharmacokinetic parameters of the drug.

Unexpectedly, it was found that in the case of using the sorption technology with aluminometasilicate as the main sorbent instead of the thermoplastic extrusion technology used in the prototype, it was possible to improve the kinetics of dissolution of the active substance from the GLF and reduce the weight of the GLF, thereby increasing the ease of administration. Moreover, the content of aluminometasilicate in the finished dosage form should be from 5 to 65% by weight of the finished dosage form. Preferably, the content of aluminometasilicate in the finished dosage form should be from 10 to 45%. Most preferably, from 21 to 28%.

In addition, the application of the above composition and technology allows a minimum change in the composition of the prototype, which allows you to rely on prototype safety studies. The safety of the newly introduced component - aluminometasilicate - is confirmed by studies (Fuji Chemical Industry Co., Ltd., Pharmacological, Toxicological and clinical data of neusilin, Neusilin A.).

The stability of the resulting preparation is confirmed by studies of accelerated aging. As a result of the studies, it was found that the quality indicators of the FDF remain within the specifications of the original drug (Kaletra), namely, in terms of foreign impurities with a shelf life equivalent to 2.5 g, ritonavir deacetylvaline - no more than 0.2%, hydroxyritonavir does not more than 0.3%, hydantoin amino alcohol - not more than 2.6%, ritonavir hydroperoxide - not more than 0.2%, O-acyl isomer of ritonavir - not more than 0.2%, oxazolidinone derivative - not more than 0.3%, single unidentified impurity - no more than 0.2%, the amount of impurities - no more than 3.5%.

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As can be seen from the attached Figs. 1 and 2, it was possible to achieve an improvement in the dissolution rate. To evaluate the obtained changes, additional numerical characteristics of the graphs were introduced: AUC area under the curve limited by the test time (given in order to empirically characterize the effect of the ratio of the dissolution rates of the studied preparations on pharmacokinetic parameters), C _1/2 - the time of transition of half of the active substance into the solution the purpose of empirical evaluation of the effect of the dissolution rate ratio on the ratio of pharmacokinetic parameters). Obviously, these characteristics cannot be directly extrapolated to known pharmacokinetic parameters, however, their improvement obviously has a positive effect on pharmacokinetic parameters, since. both active ingredients of the drug belong to the second class of BCS.

As can be seen from the graphs obtained, AUC of ritonavir (comparator drug (Kaletra)) was 5427.15, AUC of ritonavir (test drug (example 8)) - 6841.68, AUC of lopinavir (comparator drug) was 5565.378, AUC of lopinavir (test drug drug) - 6960.2490. Differences in numerical characteristics of almost 10% allow us to assert the presence of the effect of the dissolution rate on pharmacokinetic parameters.

The problem is solved by the fact that the authors of the present invention have developed a pharmaceutical composition comprising lopinavir, ritonavir, aluminometasilicate in an effective quantitative ratio of components.

Recommended dosage for adults: 400 mg lopinavir/100 mg ritonavir 2 times a day or 800 mg lopinavir/200 mg ritonavir 1 time a day for patients who have not previously received antiretroviral therapy; patients who have previously received antiretroviral therapy - 400 mg lopinavir / 100 mg ritonavir 2 times a day, it is not recommended to prescribe a single daily dose. If a decrease in patient sensitivity to lopinavir is suspected, confirmed laboratory or clinically, it is necessary to increase the dose of the drug to 500 mg lopinavir / 125 mg ritonavir when combined with nevirapine, efavirenz, nelfinavir or amprenavir. For children weighing more than 35 kg or with a body surface area greater than 1.4 ^m2 , the recommended dosage is 400 mg lopinavir/100 mg ritonavir twice daily without concomitant use of nevirapine, efavirenz, amprenavir, or nelfinavir. For children with a weight of less than 35 kg and a body surface area of up to 0.6 m ² , the doctor calculates the dose according to a special scheme individually.

In addition to the active substances and the aluminometasilicate, the pharmaceutical composition may also contain the usual excipients used in drug preparation technology, such as binders, fillers, preservatives, flow regulators, softeners, wetting agents, dispersants, emulsifiers, solvents, antioxidants and/or propellants, action prolongators; Sucker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgard, 1991.

As an excipient, the pharmaceutical composition contains one or more of the following: sugars and their derivatives (lactose, modified lactose, sucrose, glucose, mannitol, modified mannitol, sorbitol, fructose, trehalose), polysaccharides (cellulose and its derivatives, croscarmelose, starch, modified starch, sodium starch glycolate, dextrin, dextrose, dextrate, maltodextrin, calcium and its salts (phosphates, carbonates, chlorides), povidone, crospovidone, copovidones, cyclodextrins, alginic acid and its salts, saccharin 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.

On the graphs in Fig. 3 and 4 show the development field, i.e. such content of excipients, which allows to achieve an improved or equal release profile of active substances from the test product relative to the reference product.

Preferably, the pharmaceutical composition contains from 0.5 to 60 wt.% of the excipients listed above (in terms of 100 wt.% of the entire solid dosage form).

The pharmaceutical composition may contain disintegrants, such as sodium starch glycolate. Preferably, the finished dosage form contains sodium starch glycolate in an amount of from 1 to 5% (most preferably from 2 to 3%) by weight of the pharmaceutical composition. The pharmaceutical composition may contain pharmaceutically acceptable polymers which may be selected from the group consisting of water-soluble polymers, water-dispersible polymers, water-swellable polymers, and any mixtures thereof. Polymers are considered water-soluble if they form a clear, homogeneous solution in water. After dissolving at 20° C. in water at a concentration of 2% (w/v), the water-soluble polymer preferably has an apparent viscosity of 1 to 5000 mPa-s, more preferably 1 to 700 mPa-s, and most preferably from 5 to 100 mPa-s. Water-dispersible polymers are those which, when reacted with water, form colloidal dispersions rather than a clear solution. When interacting with water or aqueous solutions, water-swellable polymers usually form a rubbery gel.

For example, preferred pharmaceutically acceptable polymers can be selected from the group consisting of water-soluble polymers suitable for use in the pharmaceutical composition of the present invention, including, but not limited to, the following substances: homopolymers and copolymers of N-vinyl lactams, especially homopolymers and copolymers of N-vinylpyrrolidone,

- 3 040125 for example polyvinylpyrrolidone (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-dimethylaminoethyl methacrylate copolymers, poly(hydroxyalkyl acrylates), poly(hydroxyalkyl methacrylates); 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 ethylcellulose, hydroxyalkylcellulose, hydroxyethylcellulose, in particular hydroxypropylmethylcellulose, in particular hydroxypropylcellulose, cellulose succinates, in particular hydroxypropylmethylcellulose succinate or hydroxypropylmethylcellulose acetate succinate. In a preferred embodiment, said hydrophilic polymer comprises polyvinylpyrrolidone, polyalkylene oxide, in particular polyethylene oxide and/or cellulose derivatives, in particular hydroxypropylmethylcellulose.

Water insoluble polymers that can be used in the present invention include, but are not limited to, microcrystalline cellulose, low substituted hyprolose (hydroxypropyl cellulose).

Preferably the pharmaceutical composition contains from 10 to 70.0 wt.% polymer (in terms of 100 wt.% of the total solid dosage form).

Suitable surfactants for use in the pharmaceutical composition of the present invention include, but are not limited to, polysorbate 80 (e.g. polysorbate brand TWEEN-80), macrogol 6000 (polyethylene glycol 6000), sorbitan monoesters of fatty acids such as Span® 20 (sorbitan laurate), Span® 40 and Span® 60; or mixtures of one or more of them; polyoxyethylene derivatives of castor oil, such as polyoxyethylene glycerol triricinoleate or polyoxyl 35 castor oil (Cremophor® EL; BASF Corp.), or polyoxyethylene glycerinoxystearate, such as polyethylene glycol 40 hydrogenated castor oil (Cremophor® RH 40) or polyethylene glycol 60 hydrogenated castor oil (Cremophor® RH 60) ; alpha-tocopheryl polyethylene glycol succinate, commonly abbreviated as vitamin E TPGS; and polyalkoxylated glycerides available from Gattefosse under the tradenames Gelucire® and Labrafil®, such as Gelucire® 44/14 (lauroyl macrogol-32-glyceride obtained by transesterification of hydrogenated oil palm seed oil with PEG 1500 polyethylene glycol), Gelucire 50/13 (stearo -ylmacrogol-32-glyceride obtained by transesterification of hydrogenated palm oil with PEG 1500 polyethylene glycol) or Labrafil M1944 CS (oleoylmacrogol-6-glyceride obtained by transesterification of apricot kernel oil with PEG 300 polyethylene glycol), Softisan 601.

Preferably the pharmaceutical composition contains from 0.3 to 10.0 wt.% surfactants (in terms of 100 wt.% of the entire solid dosage form).

As a surfactant, the pharmaceutical composition may contain sorbitan laurate in an amount of 5 to 15% (most preferably 6 to 9%) by weight of the pharmaceutical composition. The pharmaceutical composition may further include one or more lubricants and glidants, which may include stearic acid and its derivatives or esters such as sodium stearate, magnesium stearate, calcium stearate and corresponding esters such as sodium stearyl fumarate; talc and silicon dioxide, respectively, but are not limited to. The amount of lubricant and/or glidant is in the range from 0.1 to 5 wt.% by weight of the composition.

The pharmaceutical composition preferably contains sodium stearyl fumarate in an amount of 0.1 to 2% (most preferably 0.8 to 1.1%) by weight of the pharmaceutical composition. The pharmaceutical composition may be used to prepare a solid dosage form.

Preferably, the solid dosage form may be in the form of powders, tablets, combined tablets, capsules, dragees, coated granules, suppositories, powders for suspensions. Dosage forms can be made in the traditional way (Pharmaceutical technology. Technology of dosage forms, 2nd ed., Moscow, 2006).

The pharmaceutical composition of the invention may be administered orally. The dosage depends on the age, condition and weight of the patient.

The examples below illustrate (without limiting the scope of claims) the most preferred embodiments of the invention, and also confirm the possibility of obtaining a pharmaceutical composition and achieving these technical results.

To obtain solid dosage forms from the respective components, the active ingredients are dissolved alone or in a mixture with excipients in an organic solvent, preferably ethanol, and applied as a solution to the sorbent; then the resulting mixture is dried. The resulting mixture is treated with excipients to obtain a mass suitable for obtaining a finished dosage form.

The mixing of the components and the preparation of the moldable mass can be carried out in different ways. Mixing can be carried out before, during and/or after drying. For example, to obtain a moldable mass, the respective components may first be dried and then mixed.

Drying is carried out in devices commonly used for this purpose. Particularly suitable are shelf dryers in an explosion-proof design.

The following examples serve to explain the invention in more detail.

Example 1

Operating Composition on and excipients one finished dosage form, mg Lopinavir 200 Ritonavir 50 Aluminometasilicate 250 Sodium starch glycolate _: 13 Sorbitana Laurate 80 Copovidone 250 colloidal silicon dioxide 40 Sodium stearyl fumarate 10 Mass for the preparation of a solid dosage form 893.0

Dissolve lopinavir, ritonavir, sorbitan laurate, copovidone in ethanol, mix with colloidal silicon dioxide and apply to aluminometasilicate. Dry the resulting mixture at 60°C, mix with sodium stearyl fumarate and sodium starch glycolate. The resulting mass is used for tableting or filling gelatin capsules.

Example 2

Operating Composition on and excipients one finished dosage form, mg Lopinavir 200 Ritonavir 50 Copovidone 250 Sorbitana Laurate 80 Aluminometasilicate 250 Crosscaramellose sodium 50 Sodium stearyl fumarate 10 mcc 298 Mass for the preparation of a solid dosage form 1188

Dissolve lopinavir, ritonavir, sorbitan laurate, copovidone in ethanol and apply to aluminometasilicate. Dry the resulting mixture at 60°C, mix with sodium stearyl fumarate, sodium crosscaramelose and microcrystalline cellulose. The resulting mass is used for tableting or filling gelatin capsules.

- 5 040125

Example 3 Operating Composition on and excipients one go- tova le- car- important form, mg Lopinavir 200 Ritonavir 50 Aluminometasilicate 250 colloidal silicon dioxide 100 Sorbitana Laurate 60 Copovidone 250 Trehalose 80 Sodium stearyl fumarate 10 Mass for the preparation of solid le- 1000 karst form

Dissolve lopinavir, ritonavir, sorbitan laurate, copovidone in ethanol and apply colloidal aluminometasilicate and silicon dioxide. Dry the resulting mixture at 60°C, mix with sodium stearyl fumarate, trehalose. The resulting mass is used for tableting or filling

latin capsules. Example 4 Active and excipients Lopinavir Ritonavir Composition per one finished dosage form, mg ~ ~ '200 50 Aluminometasilicate 250 colloidal silicon dioxide 100 Sorbitana Laurate 60 Povidone in granulation 250 Povidone for dusting 80 Sodium stearyl fumarate 10

Mass for the preparation of a solid dosage form I 000

Dissolve lopinavir, ritonavir, sorbitan laurate, povidone in ethanol and apply colloidal aluminometasilicate and silicon dioxide. Dry the resulting mixture at 60°C, mix with sodium stearyl fumarate, povidone. The resulting mass is used for tableting or filling gelatin capsules.

- 6 040125

Example 5

Operating Compound ι on and excipients one finished dosage form, mg Lopinavir Ritonavir 200 50 Aluminometasilicate 250 colloidal silicon dioxide 100 Sorbitana Laurate 60 Povidone 250 Sodium stearyl fumarate 10 Mass for the preparation of a solid dosage form 920.0

Dissolve lopinavir, ritonavir, sorbitan laurate, povidone in ethanol and apply colloidal aluminometasilicate and silicon dioxide. Dry the resulting mixture at 60°C, mix with sodium stearyl fumarate. The resulting mass is used for tableting or filling gelatin capsules.

Example 6

Operating Composition on and excipients one go- new medicine important Lopinavir form, mg 200 Ritonavir 50 Aluminometasilicate i 250 sodium starch glycolate 26 Sorbitana Laurate 80 Povidone 250 Sodium stearyl fumarate 8 Mass for the preparation of a solid dosage form 864.0

Dissolve lopinavir, ritonavir, sorbitan laurate, povidone in ethanol and apply colloidal aluminometasilicate and silicon dioxide. Dry the resulting mixture at 60°C, mix with sodium stearyl fumarate and sodium starch glycolate. The resulting mass is used for tableting or filling gelatin capsules.

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Example 7

Operating Composition on and excipients one finished dosage form, mg Lopinavir 200 Ritonavir 50 Aluminometasilicate 250 sodium starch glycolate 29 Sorbitana Laurate 80 Povidone 250 colloidal silicon dioxide 100 Sodium stearyl fumarate 9 Mass for the preparation of a solid dosage form 968.0

Dissolve lopinavir, ritonavir, sorbitan laurate, povidone in ethanol and apply colloidal aluminometasilicate and silicon dioxide. Dry the resulting mixture at 60°C, mix with sodium stearyl fumarate and sodium starch glycolate. The resulting mass is used for tableting or filling gelatin capsules.

Example 8

Operating Composition on and excipients one finished dosage form, mg Lopinavir 200 Ritonavir 50 Aluminometasilicate 250 sodium starch glycolate 20 Sorbitana Laurate 80 Povidone 250 colloidal silicon dioxide thirty Sodium stearyl fumarate 10

Mass for preparing a solid dosage form 890.0

Dissolve lopinavir, ritonavir, sorbitan laurate, povidone in ethanol and apply colloidal aluminometasilicate and silicon dioxide. Dry the resulting mixture at 60°C, mix with sodium stearyl fumarate and sodium starch glycolate. The resulting mass is used for tableting or filling gelatin capsules.

Claims (12)

CLAIM 1. A pharmaceutical composition with activity against HIV infection, including lopinavir, ritonavir in an effective amount on a sorbent, characterized in that it contains aluminometasilicate as a sorbent in an amount of 21 to 28% by weight of the pharmaceutical composition. 2. Pharmaceutical composition according to claim 1, characterized in that it additionally contains a glidant, a surfactant and a disintegrant. 3. Pharmaceutical composition according to claim 2, characterized in that it contains sodium stearyl fumarate as a glidant. 4. Pharmaceutical composition according to claim 3, characterized in that it contains sodium stearyl fumarate in an amount of 0.1 to 2% by weight of the pharmaceutical composition. -8040125 5. Pharmaceutical composition according to claim 4, characterized in that it contains sodium stearyl fumarate in an amount of 0.8 to 1.1% by weight of the pharmaceutical composition. 6. Pharmaceutical composition according to claim 2, characterized in that it contains sorbitan laurate as a surfactant. 7. Pharmaceutical composition according to claim 6, characterized in that it contains sorbitan laurate in an amount of 5 to 15% by weight of the pharmaceutical composition. 8. The pharmaceutical composition according to claim 7, characterized in that it contains sorbitan laurate in an amount of 6 to 9% by weight of the pharmaceutical composition. 9. Pharmaceutical composition according to claim 2, characterized in that it contains sodium starch glycolate as a disintegrant. 10. Pharmaceutical composition according to claim 9, characterized in that it contains sodium starch glycolate in an amount of 1 to 5% by weight of the pharmaceutical composition. 11. Pharmaceutical composition according to claim 9, characterized in that it contains sodium starch glycolate in an amount of 2 to 3% by weight of the pharmaceutical composition. 12. The use of a pharmaceutical composition according to any one of claims 1 to 11 for the preparation of a solid dosage form for the treatment of HIV infections.