WO2018056865A1

WO2018056865A1 - Pharmaceutical composition for treating hiv infection

Info

Publication number: WO2018056865A1
Application number: PCT/RU2017/000622
Authority: WO
Inventors: Елена Сергеевна ХАЗАНОВА; Сергей Юрьевич НОГАЙ; Дмитрий Владимирович ЯКОВЛЕВ
Original assignee: Общество С Ограниченной Ответственностью Изварино Фарма
Priority date: 2016-09-21
Filing date: 2017-08-25
Publication date: 2018-03-29
Also published as: CN109789140A; RU2619840C1

Abstract

The invention relates to the field of the pharmaceutical chemical industry. The present pharmaceutical composition for treating HIV infection comprises lopinavir and ritonavir in an effective amount, and a polymer. The pharmaceutical composition is produced by extrusion. The composition comprises, as the polymer, a matrix polymer consisting of PEG 6000 / vinylcaprolactam / vinyl acetate, at 5 to 25 % of the mass of the pharmaceutical composition, in combination with copovidone, at 45 to 65 % of the mass of the pharmaceutical composition. This invention makes it possible to broaden the range of available drugs with improved pharmacokinetic properties.

Description

Pharmaceutical composition for treating HIV infection

The invention relates to the field of the pharmaceutical industry.

HIV protease (PI) inhibitors, which include lopinavir and ritonavir, are substances with 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 inhibitors, protease does not fulfill its function, and viral particles are formed that are not able to infect new cells. PIs often have a side effect on the digestive tract. With prolonged use, lipid metabolism disorders of varying severity and the development of lipodystrophy are possible.

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

It is known that almost all HIV protease inhibitors are sparingly soluble in water. In this regard, technological difficulties arise in the process of creating finished dosage forms based on these substances. In addition, it is a very difficult task to select the composition of excipients in such a way as to improve the pharmacokinetic parameters of the finished dosage form and, accordingly, the bioavailability of the APS, as well as increase the comfort of taking the drug by reducing the weight of the finished dosage form.

The prior art drug Kaletra® tablets coated film coating (Lopinavir 200 mg + Ritonavir 50 mg) ”produced by Abbott GmbH and Co. KG, Germany, which is described in patent EA 011924 and adopted as a prototype.

As follows from patent EA 0011924, the authors attempted to improve the bioavailability of the solid dosage form of lopinavir + ritonavir. This problem was solved by introducing into 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 weight dosage form, as well as the use of thermoplastic extrusion technology.

There is a continuing need to develop improved solid dosage forms. In particular, polymeric carrier compositions for the formation of solid dispersions are in demand, which exhibit a higher ability to dissolve the drug and / or make it possible to reduce the melt viscosity without compromising the mechanical properties and storage stability of the dosage form.

One way to improve the bioavailability of sparingly soluble substances is to use melt extrusion technology. Mandatory steps of this technology are the melting or melting of a mixture of a polymer binder and an active pharmaceutical ingredient and, possibly, but not necessarily, additional excipients and the formation of an extrudate from the melt. In the following stages, the labor is processed, in order to prepare for the formation of the finished dosage form, by any suitable methods. As a result of the process using this technology, a solid solution of active pharmaceutical ingredient in the matrix. There are a number of difficulties in the selection of a suitable composition of excipients and technological parameters. Constant research is underway to develop new compositions suitable for solving the problem.

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

WO 00/57854 discloses mechanically stable pharmaceutical oral dosage forms which contain at least one active compound, at least one thermoplastic forming matrix forming adjuvant, and from more than 10% to 40% May. a surfactant that 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.

Abbreviations Used

HLB - Hydrophilic-lipophilic balance

BCS is a biopharmaceutical classification system.

IP - Protease Inhibitors

HIV Human Immunodeficiency Virus

PEG - Polyethylene Glycol

SAXR - small-angle X-ray scattering

APS is an active pharmaceutical substance Brief Description of the Figures

Figure 1. The analysis of the degree of crystallinity of the pharmaceutical composition according to example 2 analyzed using small angle x-ray scattering - SAXS (Anton Paar). 1 - a mixture of polymers and APS (extrudate), 2 - lopinavir, 3 - a mixture of polymers included in the extrudate.

Figure 2. The analysis of the degree of crystallinity of the pharmaceutical composition according to example 2 analyzed using SAXS (Anton Paar). 1 - a mixture of polymers and APS after extrusion (extrudate) after 6 months of storage, 2 - lopinavir, 3 - a mixture of polymers after extrusion after 6 months of storage, 4 - ritonavir

Figure 3. The study of the kinetics of the release of lopinavir (Figures ZA, V, D, G) and ritonavir (Figures ST, G, E, 3) from the studied drug (PI) - Lopinavir and Ritonavir (solid line), tablets, film-coated from example 5, 7, 8 and 4, respectively, in comparison with the Comparative Preparation (PS) - Kaletra (dotted line). The ordinate indicates the amount of substance transferred to the solution in%, and the abscissa indicates the time of sampling, min.

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

It was unexpectedly discovered that if a matrix polymer consisting of PEG 6000 / vinylcaprolactam / vinyl acetate in combination with copovidone in certain proportions was used as the main polymer, instead of those used in the prototype, it was possible to improve the kinetics of dissolution of the active substance from GLF. Moreover, the content of copovidone in the finished dosage form should be from 5 to 65% by weight of the finished dosage form, and the matrix polymer PEG 6000 / vinylcaprolactam / vinyl acetate - from 5 to 55%. Preferably, the copovidone content of the finished dosage form should be from 45 to 65%, and PEG 6000 / vinylcaprolactam / vinyl acetate should be from 5 to 25%. In the case of a change in the content of these substances or the exclusion of one of the substances from the finished dosage form, it was not possible to improve the kinetics of dissolution of the active substances (see Figure ZD, E, G and 3).

As can be seen from the attached figures ZA and ST, it was possible to improve the dissolution rate. To evaluate the changes obtained, additional numerical characteristics of the graphs were introduced: AUC - area under the curve, limited by the test time (used to empirically characterize the influence of the ratio of dissolution rates of the studied drugs on pharmacokinetic parameters), C _t - half transition time active substance into the solution (introduced for the purpose of empirical assessment of the influence of the ratio of the rate of dissolution 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, because both active ingredients of the drug belong to the second class of BCS.

As can be seen from the obtained graphs, the AUC of ritonavir (comparison drug) was 5842.50, AUC of ritonavir (test drug) was 6204.75, AUC of lopinavir (comparison drug) was 5986.50, and AUC of lopinavir (test drug) was 6387.00 . The differences in the numerical characteristics of almost 10% suggest the presence of the influence of the dissolution rate on the pharmacokinetic parameters.

As can be seen from the obtained graphs, Syu ritonavir (drug of comparison) was 28 minutes, C 1/2 of ritonavir (test drug) was 25 minutes, C 1/2 of lopinavir (comparison drug) was 27 minutes, and C pinavira (test drug) - 23 minutes. The difference in the time it takes for half of the active substance to enter the solution between the reference drug and the test drug allows us to state the improvement in the pharmacokinetic parameters of the test drug relative to the comparison drug.

The problem is solved by the fact that the authors of the present invention developed a pharmaceutical composition comprising lopinavir, ritonavir, a matrix polymer consisting of PEG 6000 / vinyl-prolactam / vinyl acetate / in combination with copiform and pharmaceutically acceptable excipients in a certain quantitative ratio components.

As the matrix polymer, PEG 6000 / vinylcaprolactam / vinyl acetate can be used.

Along with the active substances and the matrix polymer, in combination with the copiform, the pharmaceutical composition may contain conventional excipients adopted in the preparation of medicines, such as binders, fillers, preservatives, flow regulators, emollients, wetting agents , dispersing agents, emulsifying agents, solvents, antioxidants and / or propellants, prolonging agents of action of Sucker et al .: Pharmazeutische Technologie, Thieme-Verlag, Stuttgard, 1991.

As a filler, the pharmaceutical composition contains one or more of the following substances: sugars and their derivatives (lactose, modified lactose, sucrose, glucose, mannitol, modified mannitol, sorbitol, fructose), polysaccharides (cellulose and its derivatives, starch, modified starch, starch, dextrin, dextrose, dextrate, maltodextrin, calcium and its salts (phosphates, carbonates, chlorides), 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.

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

In addition to the matrix polymer, the finished dosage form may contain other pharmaceutically acceptable polymers that can be selected from the group consisting of water soluble polymers, water dispersible polymers and 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% (May / vol.), The water-soluble polymer preferably has a 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 materials: Ν-vinyl lactam homopolymers and copolymers, especially homopolymers and copolymers of Ν-vinylpyrrolidone, for example polyvinylpyrrolidone (PVP), copolymers of Ν-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; by- lyacrylates 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); polyacryl yl amides; 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 methyl cellulose and ethyl cellulose, hydroxyalkyl cellulose, hydroxyethyl cellulose, in particular hydroxypropyl methyl cellulose, in particular hydroxypropyl cellulose, cellulose succinate, in particular hydroxyethyl cellulose. In a preferred embodiment, said hydrophilic polymer comprises polyvinyl pyrrolidone, polyalkylene oxide, in particular polyethylene oxide and / or cellulose derivatives, in particular hydroxypropyl methyl cellulose.

Water-insoluble polymers that may be used in the present invention include, but are not limited to, the following materials: 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 entire solid dosage form).

Surfactants suitable for use in the pharmaceutical composition of the present invention include, but are not limited to the following substances: polysorbate 80 (e.g., TWIN-80 polysorbate), macrogol 6000 (polyethylene glycol 6000), sorbitan fatty acid monoesters, such as Span® 20, Span® 40 and Span® 60; or mixtures of one or more of them; polyoxyethylene derivatives of castor oil, for example polyoxyethylene glycerol triticinoleate or polyoxyl 35 castor oil (Cremophor® EL; BASF Corp.), or polyoxy ethylene glycerol oxystearate such as polyethylene glycol 40 hydrogenated castor oil (Cremophor® RH 40) or polyethylene glycol 60 oil (Cremophor® RH 60); alpha-tocopheryl polyethylene glycol succinate, which is usually abbreviated as Vitamin E GSH C; as well as polyalkoxylated glycerides sold by Gattefosse under the trade names Gelucire ^® and Labrafil ^® , for example Gelucire ^® 44/14 (lauroyl macrogol-32-glyceride obtained by transesterification of hydrogenated oil of palm oil seeds with PEG 1500 polyethylene glycol) / Gelucire ^® 13 stearo-ilmacrogol-32-glyceride obtained by transesterification of hydrogenated palm oil with PEG 1500 polyethylene glycol) or Labrafil Ml 944 CS (oleoyl macrogol-6-glyceride obtained by transesterification of oil from polyethylene glycol apricot kernels PEG 300 brand name), 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).

The finished dosage form 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 the corresponding esters, such as : sodium fumarate stearyl; talc and silicon dioxide, respectively, but are not limited to. The amount of lubricant and / or glidant is preferably in the range from 0.25% to 5% by weight of the composition.

Preferably, the drug can be made in in the form of powders, tablets, combination tablets, capsules, dragees, coated granules, suppository, powders for the preparation of suspensions. Dosage forms can be performed in the traditional way ("Pharmaceutical technology. Technology of dosage forms", 2nd ed., Moscow, 2006).

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

The following examples 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 the indicated technical results.

In order to obtain solid dosage forms from the corresponding components at an elevated temperature, that is, at a polymer softening temperature or a higher temperature of at least 70 ° C., a moldable mass is obtained, which is then cooled, if necessary, after the molding step is completed. Typically, the melt temperature is in the range of from about 40 ° C to about 200 ° C, preferably from about 50 ° C to about 160 ° C.

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 heating of some or all of the components of the mass. For example, in order to obtain a moldable mass, the respective components may first be mixed and then heated. In addition, they can be mixed and heated at the same time. Often, additional homogenization of the moldable mass is carried out to provide a highly dispersed distribution of the biologically active substance.

Heating is carried out in devices commonly used for this purpose. Especially suitable are heated extruders or mixers, in particular continuous mixers (for example, such as ORP, CRP, AP or DTB from List, type Reaktotherm from Krauss-Maffei or Baker-Perkins worm mixers from Buss), two-blade two-tray mixers (trough mixers), plunger (internal) mixers or rotor / stator systems (e.g. PSA Dispax).

As extruders, single-screw extruders, comb screw extruders, as well as multi-screw, in particular double-screw extruders, if necessary equipped with kneading disks, with unidirectional or multidirectional rotation of the worms, can be used. Werner u twin screw extruders are particularly preferred. Pfleiderer of the ZSK range.

The mass in the extruders or mixers, depending on their design, is loaded in the usual way continuously or periodically. Powdered components can be loaded by gravity, for example, using differential metering weights. Plastic masses can be fed directly from the extruder or by means of a gear pump, the use of which is preferred in case of high viscosity and pressure. Liquid media can be dosed with a suitable pump.

The resulting masses have a pasty or pasty consistency. They are usually subjected to molding. In this case, depending on the type of forming tool and the molding method, the most diverse form can be given to the molded masses. For example, in the case of using an extruder, the extruded strand can be molded between one tape and one roll, between two tapes or two rolls, as described in European patent application EP-A-358105, or by processing on a calender equipped with two forming rolls - mi (see, for example, European patent application EP-A-240904). By extrusion and hot or cold cutting of an extruded tow, for example, fine granules can be obtained. In addition, the cooled mass may be milled to a powder state and subsequently conventionally compressed to form tablets. In addition, auxiliary substances intended for tabletting can be used.

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

Example 1

Mix PEG 6000 / vinylcaprolactam / vinyl acetate, span 60, colloidal silica and add Span 20, homogenize, add lopinavir and ritonavir and mix.

Extrude the resulting mixture at 135 ° C, powder, and tablet.

Example 2

Mix PEG 6000 / vinylcaprolactam / vinyl acetate, span 60, colloidal silicon dioxide and add span 20, homogenize, add lopinavir and ritonavir and mix.

Extrude the resulting mixture at a temperature of 105 to 145 ° C, dust, and tablet. Example 3

Mix PEG 6000 / vinylcaprolactam vinyl acetate, colloidal silicon dioxide add span 20 and crossscaramellose, homogenize, add lopinavir and ritonavir and mix.

Extrude the resulting mixture at a temperature of 105 to 145 ° C, dust, and tablet.

Example 4 Active Composition for one Composition for one and auxiliary substances tablet, mg tablet, mg

E stroudate

Loshavir 200 100

Ritonavir 50 25

PEG 626 313

60 (U / vinylcaprolactam / vinyl acetate

Span 20 80 30

Crossscaramellose 20 10

Colloidal silicon dioxide 12 6

Dusting

Sodium stearyl fumarate 12 6

Copovidone 60 30

Softisan 601 20 10

Colloidal Silicon Dioxide 8 4

Tablet weight 1068.0 534.0

Mix PEG 6000 / vinylcaprolactam / vinyl acetate, colloidal silicon dioxide add span 20 and crossscaramellose, homogenize, add lopinavir and ritonavir and mix.

The resulting mixture was extruded at a temperature of 105 to 145 ° C, dusted, and tabletted.

Example 5

Name of ingredient Composition per tablet, mg E stroudate:

Lopinavir 200.0

Ritonavir 50.0

Copovidone 726.0

PEG 80.0

6000 / vinylcaprolactam / vinylac

etat

Dusting

Sorbitan Laurate 60.0

Sorbitan stearate 40.0

Silicon Colloidal Dioxide 20.0

Sodium stearyl fumarate 12.0

The weight of the core tablets 1188,0

Mix PEG 6000 / vinylcaprolactam / vinyl acetate and copovidone, homogenize, add lopinavir and ritonavir and mix.

Example 6

The resulting mixture is extruded at a temperature of 135 ° C, powder, tablet to tiroat.

Example 7

The resulting mixture is extruded at a temperature of 120 ° C, dusted, tableted.

Example 8

Sorbitan Stearate 20.0

Silicon Colloidal Dioxide 10.0

Sodium stearyl fumarate 6.0

The mass of the core tablets 594.0

Mix PEG 6000 / vinshka11rolactam / vinyl acetate and copovidone, homogenize, add lopinavir and ritonavir and mix.

Extrude the resulting mixture at a temperature of 125 ° C, powder, and tablet.

Example 10

The extrudate (Example 1) and the components included in the extrudate were analyzed using SAXS for crystallinity of materials. SAXSpace - Small Angle X-ray Scattering (SAXS or SAXS) is a non-destructive method for studying the crystallinity and orientation of materials, the stability of dispersions.

The absence of characteristic peaks in the extrudate in the range of 5-10 degrees indicates that the APS is in an amorphous state in the freshly prepared extrudate (Figure 1) and after 6 months of storage of the exudate at 20 ° C / 60HD (Figure 2) .

Example 11

The kinetics of dissolution of the test drug from example 5 (Figure 3 A and B), 7 (Figure 3 C and D), 8 (Figure 3 D and E) and 4 (Figure 3 G and 3) in comparison with the original drug.

Claims

Claim

1. A pharmaceutical composition for the treatment of HIV infection obtained by extrusion and comprising lopinavir, ritonavir in an effective amount and a polymer, characterized in that the polymer contains a matrix polymer consisting of PEG 6000 / vinylcaprolactam / vinyl acetate from 5 to 25% by weight of the pharmaceutical composition in combination with copovidone, from 45 to 65% by weight of the pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, characterized in that the extrusion is carried out with heating.

3. The pharmaceutical composition according to claim 2, characterized in that the temperature of the extrusion is from 105 to 145 ° C.

4. The pharmaceutical composition according to claim 3, characterized in that the temperature of the extrusion is 135 ° C.

5. The pharmaceutical composition according to claim 1, characterized in that it further comprises a glidant, a surfactant and a disintegrant.

6. The pharmaceutical composition according to claim 5, characterized in that it contains sodium stearyl fumarate as a glidant.

7. The pharmaceutical composition according to claim 5, characterized in that as disintegrant contains crossscaramellose.

8. The pharmaceutical composition according to claim 5, characterized in that as a surfactant contains a mixture of Span 60 and Span 20.

9. The pharmaceutical composition according to claim 5, characterized in that, as a surfactant, it contains a mixture of Softisan 601 and Span 20.