UA111422U - A METHOD OF MANUFACTURING PHARMACEUTICAL COMPOSITION FOR ORAL APPLICATION CONTAINING AN ANTIRETROVIRUS SUBSTANCE COMBINATION - Google Patents

Abstract

A method of manufacturing a pharmaceutical composition comprises the steps of: a) mixing tenofovir disoproxil fumarate (TDF) and emtricitabine with one or more pharmaceutically acceptable excipients such as fillers, binders, disintegrants; b) the mixture obtained in step (a) is subjected to wet granulation in the presence of a pharmaceutically acceptable humectant; c) the wet granules are dried and optionally calibrated; d) the resulting granulate is mixed with one or more pharmaceutically acceptable excipients such as fillers, binders, disintegrants; e) dusted with one or more lubricants and tableted; f) optionally apply a film sheath.

Description

Mn,

E s no A, in iy

SvNioEMzOz5

Molecular weight - 247.25 1) 4-atipo-5-Yanogo-1-K2B8, 55)-7-(nudgokhuteiNu!)-1,3-ohaipiyoap-5-uCe(1H)-rugitiaipope; 2) (-)-siv-4-atipo-5-Piogo-1-(2-pudgohuteinu!)-1,3-ohaipioiap-5-uUC-(1H)rugitididip-2-ope; 3) (-)-(28, 55)-5-Yanogo-1-(2-nuagohuteinu!1)-1,3-ohaipiyoap-5-uCsuyuvipe; 4) (-)-p-2,3'-dideohu-5-Piogo-3'-Ipiasuyaipe.

Emtricitabine is a white or off-white powder, sparingly soluble in water and methanol. It shows polymorphism. Emtricitabine has two chiral centers and therefore exhibits isomerism. pH 1 95 of the aqueous solution is 4.73. A little hygroscopic. The melting point is 136-140"C.

Emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI) for the treatment of HIV infection in adults. Emtricitabine is an analogue of cytidine. Emtricitabine works by inhibiting reverse transcriptase, the enzyme that copies HIV RNA into new viral DNA.

Emtricitabine is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate, which is responsible for inhibiting HIV-1 reverse transcriptase. It competes with the natural substrate deoxycytidine kinase 5'-triphosphate and is included in the nucleation of viral DNA, as a result of which premature chain breakage occurs. Therefore, emtricitabine inhibits the activity of HIV-1 reverse transcriptase (RT) and, competing with the natural substrate /5'-triphosphate deoxycytidine kinase, and due to its incorporation into viral DNA. By interfering with HIV-1 reverse transcriptase, emtricitabine can help reduce the amount of HIV or "viral load" in a patient's body and can indirectly increase the number of immune system cells (called T-cells or T-cells). Both of these factors are associated with healthier immune systems and a reduced likelihood of serious illness.

Emtricitabine is rapidly absorbed (mean absolute bioavailability 93 95 for capsules and 75 95 for solution), food does not affect absorption. Protein binding is very low (less than 4 9b).

The method of obtaining emtricitabine and its intermediate intermediates is described in the following publications: ЕР2377862, ЕР1608644, МО2012131541, МО2010055526, ММО2011107920.

A pharmaceutical composition containing tenofovir/emtricitabine/darunavir/ritonavir is known

MO/2015/155673 "OMIT BROBASE ROVM SOMRVAIIIBIM EMTVISITAVIME, TEMOROMIV, OAVOMAMIV

AMO VITOMAMIV", publication date 15.10.2015.

Known pharmaceutical composition containing tenofovir/"efavirenz/"emtricitabine 05 20150174147 "OMITAVM RNAVMASETSSHTISAI VOBASE EGOVM", publication date 06.25.2015.

Tenofovir disoproxil fumarate)- and -M - o I; g Mn, x y? y M 0-4 o-R M 0-7 2--Y M e

N ki, he

Se9NZOM5O1TOR. C4H4O4

Molecular weight - 635.51.

1) (1 8)-2-(6-Atipo-9H-rigip-9-uI)-1-teipuieiptohu|tetyuPrpozrpopis asia isorgohititagaie 2) (8)-9--2-rpozrpopoteipohurgoru)adepipe disorgohiiitagaie

Tenofovir disoproxil fumarate belongs to purines and purine derivatives.

Tenofovir disoproxil fumarate is a white or white with a yellowish tinge powder, moderately soluble in methanol and ethanol. Tenofovir disoproxil fumarate exhibits isomerism because it contains one chiral center. Tenofovir disoproxil fumarate also exhibits polymorphism.

Tenofovir disoproxil fumarate is used in combination with other antiretroviral drugs to treat HIV-1 infection.

Tenofovir disoproxil fumarate belongs to a class of antiretroviral drugs known as Nucleotide Reverse Transcriptase Inhibitors (NRTIs), which block reverse transcriptase, an enzyme that is critical to the production of virus in HIV-infected people.

Tenofovir disoproxil fumarate is an acyclic phosphonate nucleoside diester, an analogue of adenosine monophosphate. Initial diester hydrolysis is required for conversion to tenofovir and subsequent phosphorylation by cellular enzymes to form tenofovir diphosphate.

Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerase alpha, VD, and mitochondrial

DNA polymerases in

Tenofovir inhibits the activity of HIV reverse transcriptase, competing with the natural substrate deoxyadenosine 5'-triphosphate, and after inclusion in DNA, by breaking the DNA chain. In particular, the drugs are analogues of natural deoxynucleotides necessary for the synthesis of viral DNA, and they compete with natural deoxynucleotides for inclusion in the growing DNA chain of the virus. Nevertheless, unlike natural deoxynucleotides, the substrates, MATI, and MEVTs (nucleoside/nucleotide reverse transcriptase inhibitors) do not have a 3'-hydroxyl group of deoxyribose. As a result, after incorporation into MATI or MIVTI, the next incoming deoxynucleotide cannot form the next 5-3" phosphodiester bond required for DNA chain extension. Thus, when METI or MIVTI is incorporated, viral DNA synthesis ceases, a process known as circuit breaker.

The bioavailability of tenofovir when administered orally is about 25 95, the use of the drug with food containing 40 95 to 50 95 fat increases the bioavailability to about 40 95.

The method of obtaining tenofovir disoproxil fumarate and its intermediate intermediates is described in the following publications. 058759515, M/O2007013086, M/O2009064174, MO2008140302, ЕР2545063,

MO2015108780.

A known pharmaceutical composition containing tenofovir or its stereoisomers, a pharmaceutically acceptable salt, hydrate or solvate and a pharmaceutically acceptable carrier - 05 20150225433 "TGEMOROMIV REOYUNOS AMO RNAVMASESHTISAI O5EB5 TNEREORE", publication date 08/13/2015

To date, such drugs are known on the pharmaceutical market as: - Atripla - film-coated tablets, Mo 30 in vials containing the active substances efavirenz - 600 mg / emtricitabine 200 mg / tenofovir disoproxil fumarate 300 mg and auxiliary substances croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, Opadray II white 85E18422 (polyethylene glycol 3350, polyvinyl alcohol, talc, titanium dioxide (E 171)); - Viradei - film-coated tablets containing the active substances efavirenz 600 mg / emtricitabine 200 mg / tenofovir disoproxil fumarate 300 mg and auxiliary substances microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, corn starch, hypromellose, sodium lauryl sulfate, magnesium stearate, iron oxide red (E 172), powder AMV 80Mu54485 pink (polyvinyl alcohol, titanium dioxide (E 171), talc, lecithin, xanthan gum, iron oxide yellow (E 172), iron oxide red (E 172)), powder AMV 80M /56843 brown (polyvinyl alcohol, titanium dioxide (E 171), talc, iron oxide red (E 172), lecithin, xanthan gum); - Maktrivir - film-coated tablets containing the active substances efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg and auxiliary substances: microcrystalline cellulose (Amise! pH 101); microcrystalline cellulose (Amise!Y pH 102); croscarmellose sodium; hydroxypropyl cellulose; sodium lauryl sulfate; magnesium stearate; pregelatinized starch;

Oraadgu I! 85694172 Rapk: polyvinyl alcohol, titanium dioxide (E 171), macrogol 4000, talc, iron oxide red (E 172), iron oxide black (E 172); - Complera - film-coated tablets containing the active substances emtricitabine 200 mg / rilpivirine 25 mg (in the form of hydrochloride) / tenofovir disoproxil 245 mg (in the form of fumarate) and auxiliary substances: microcrystalline cellulose; lactose, monohydrate; povidone; gelatinized starch; polysorbate 20; croscarmellose sodium; magnesium stearate; hypromellose; titanium dioxide (E 171); triacetin

All of the listed preparations contain three active components, as well as surfactants, such as sodium lauryl sulfate and Tween 20, as part of auxiliary substances.

Therefore, there was a need to develop a medicinal product in the form of film-coated tablets, which would contain a combination of emtricitabine 200 mg/ tenofovir disoproxil fumarate 300 mg and which would not contain surfactants, especially such as sodium lauryl sulfate, as it is known strong allergenic properties.

The task of this useful model is to select the optimal manufacturing technology and parameters of the technological process to create an economically feasible and reproducible, industrially suitable method of manufacturing this medicinal product in the form of tablets, optionally covered with a film coating.

In a preferred embodiment of this utility model, a stable dosage form for oral administration is prepared by a method comprising the steps of: a) mixing tenofovir disoproxil fumarate (TDF) and emtricitabine with one or more pharmaceutically acceptable excipients, such as excipients, binders substances, disintegrants;

B) the mixture obtained at stage (a) is subjected to wet granulation in the presence of a pharmaceutically acceptable humectant; c) wet granulate is dried and optionally calibrated; a) the resulting granulate is mixed with one or more pharmaceutically acceptable excipients, such as fillers, binders, disintegrants; e) dusted with one or more lubricants and tableted; i) it is not necessary to apply a film cover.

The pharmaceutical composition, according to this useful model, is presented in the form of tablets, optionally covered with a film shell, which contains the active substances emtricitabine and tenofovir disoproxil fumarate, and may also optionally contain at least one substance selected from the group: fillers, binders, disintegrants, lubricants, solvents, adhesives, film formers, plasticizers, pigments and dyes or combinations thereof.

The following can be used as fillers: potato starch; corn starch; partially pregelatinized starch; microcrystalline cellulose; powdered cellulose; silicified microcrystalline cellulose (Rho5om); lactose monohydrate; lactose anhydrous; eyap as (lactose monohydrate and corn starch); I tsairgez5 Y SE (lactose monohydrate and povidone); Seiyasiose 80 (lactose monohydrate - cellulose powder); And asiozee, brgau-Ogied; dextrate; dextrin; dextrose; fructose; maltodextrin; maltose; mannitol; polydextrose; sorbitol; sucrose; magnesium carbonate; magnesium oxide; calcium carbonate; calcium lactate; calcium phosphate dibasic anhydrous; tribasic calcium phosphate or combinations.

The following binders can be used: microcrystalline cellulose; powdered cellulose; ethyl cellulose; hydroxyethyl cellulose; hydroxyethyl methylcellulose; hydroxypropyl cellulose; hypromellose (hydroxypropylmethylcellulose); methyl cellulose; povidone; copovidone; dextrate; dextrin; maltodextrin; glucose; polydextrose; sorbitol; sucrose; gelatin, lactose monohydrate; And asyose,

Zrgau-Ogied; potato starch; corn starch; partially pregelatinized starch or combinations.

Disintegrants can be used: calcium carboxymethyl cellulose; sodium carboxymethyl cellulose; croscarmellose sodium; microcrystalline cellulose; powdered cellulose; crospovidone (KoiPaop Si; Koidop SI-M; Roiuriazdope XI; Roiuriazhadope XI-10); sodium starch glycolate; pregelatinized starch; corn starch; potato starch or their combinations.

As lubricants can be used: magnesium stearate; calcium stearate; stearic acid; talc; hydrogenated castor oil; glycerine behenate (Sotriot! 888); glyceryl monostearate; glyceryl palmitostearate; poloxamer; polyethylene glycol; sodium stearyl fumarate or combinations thereof.

The following substances can be used to create adhesion: microcrystalline cellulose; lactose monohydrate or their combinations.

As film formers can be used: hypromellose; polyvinyl alcohol; partially hydrolyzed polyvinyl alcohol; hydrolyzed polyvinyl alcohol; hydroxypropyl cellulose; hydroxyethyl cellulose; hydroxypropylmethylcellulose; polyethylene glycol; macrogol; copovidone or combinations thereof.

As plasticizers can be used: triacetin; tributyl citrate; triethyl citrate; acetyl tributyl citrate; acetyl triethyl citrate; diethyl phthalate; dimethyl phthalate; dibutyl phthalate; polyethylene glycol (macrogol: 2000; 3000; 3350; 4000; 4600; 8000); propylene glycol or their combinations.

As pigments and dyes can be used: titanium dioxide; ES Brice 41 (VgiPapi Biye ESE);

Eras rie 52 (Ipaidoiipe); OS riye 24 (Airnagytpe GS); 080 Binet 59 (Ipdappingepe Brije); EOVS swarms Ya

IaKke (VpiiShapi Bishe ESE); ROS riye 52 IaKe (Ipaidoiipe); 08 Biye 24 IaKe (AIrpagigipe RS) or their combinations.

In another version of this useful model, the problem is solved by the fact that the claimed pharmaceutical composition in the form of film-coated tablets contains emtricitabine; tenofovir disoproxil fumarate; pregelatinized starch; microcrystalline cellulose; magnesium stearate; lactose monohydrate; croscarmellose sodium; Oraigu II ViIne (lactose monohydrate, hypromellose; titanium dioxide; triacetin; ROS Visey2 aluminum varnish).

Purified water can be used as a solvent or moisturizer.

The terms used in this utility model are commonly used and known to those skilled in the art.

The following example describes an embodiment of this utility model, but is not limited thereto.

Example 1 dosed unit per batch

With (Starch pregelatinized.//-/:/ | 20111111 180 6 | Croscarmellose sodium /-/-:// 777771 | Ї1111111111126111111111 1960 8 | OraiguyVichme 77777771 Ї111111111115407777 | 480

Tenofovir disoproxil fumarate is sifted through a 10-mesh sieve, emtricitabine, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and pregelatinized starch are sifted through a 30-mesh sieve. Then the sifted components for this operation are loaded into the container of the binary mixer of the appropriate volume and mixed with each other for 2 minutes, then the resulting mixture is sifted through a sieve with a hole size of 10 theses.

The sifted mixture is loaded into a high-speed mixer-granulator and continues to be mixed for 15 minutes. Then, pre-weighed purified water is added to the resulting mixture with constant slow stirring for 2 minutes. Then continue mixing for 1 minute. The resulting mass is calibrated through a sieve-calibrator for wet granulation into the container of a fluidized bed dryer.

The obtained wet granulate is dried in a fluidized bed dryer at an inlet air temperature of 60-10 C to obtain a granulate with a residual moisture of 0.75-2.25 96. The obtained granulate is crushed and sieved using a sieve-granulator for dry granulation, through a sieve with a size opened 20 theses.

Sieve the 1st part of croscarmellose sodium and the 1st part of microcrystalline cellulose through a 30 mesh sieve.

A known amount of the obtained granulate is loaded into the container of the binary mixer of the appropriate volume, I part of croscarmellose sodium and I part of microcrystalline cellulose are sifted and mixed for 10 minutes.

Magnesium stearate is sifted through a sieve with a mesh size of 40 teva.

Magnesium stearate is added to the resulting mixture and powdering is carried out for 4 minutes.

The resulting tablet mass is pressed on a Retse 1200 rotary tablet press to obtain core tablets of an oval (capsule) shape, with a biconvex surface, white or almost white in color, length 19 mm x 0.3 mm, width 8.5 mm 50.2 mm and height from 6.30 to 7.30 mm, average weight 1.0 g 0.05 g.

Tablets-cores after pressing are examined for abrasion (fragility) on the EMU/EKA TAV 200 device, resistance to crushing (hardness) on the EVMUEKA TVN 450 M/TO device, disintegration time was determined on the EVM/EKA 2T-7X device.

These indicators have the following limits: - abrasion (fragility) - 0.01-0.03 9o; - resistance to crushing (hardness) - not less than 200-240 N, - disintegration time (disintegration time) of core tablets: about 6-8 minutes.

The resulting tablets-cores are optionally coated with a film coating in a standard way in a perforated drum of the Repogaied UOgyt Soaieg type ready-made system in the form of a suspension of Oraag I

Vignat, to obtain tablets of oval (capsule-like) shape, biconvex, covered with a film shell from light blue to blue in color, with an average weight of 1.025 g 0.052 g.