RU2367472C1 - Parenteral preparation and method for making thereof - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: pharmaceutical composition for making a parenteral preparation contains a pharmaceutical agent, a water-soluble polymer, a nonpolymeric additive and a solvent. The water-soluble polymer is chosen from the group: dextran, gelatin, 2-hydroxyethy starch, poly(N-vinylpyrrolidone), human blood serum albumin or their mixture. The nonpolymeric additive is chosen from the group: (C₁₀-C₁₈)acyl-sorbite, oligooxyethylene(C₁₀-C₁₈)acyl-sorbite, (C₁₀-C₁₈)alkyl oligooxyethylene glycol ester. The solvent represents mixed water and ethanol, or dimethyl sulphoxide, or N-methyl-2-pyrrolidone, or 2-pyrrolidone. The pharmaceutical agent, said water-soluble polymer, nonpolymeric additive and residual solvent are found in the preparation as a noncovalent complex.

EFFECT: improved bioavailability of the pharmaceutical agents and therapeutic dose decline.

2 cl, 1 dwg, 1 tbl, 1 ex

Description

The invention relates to pharmaceuticals, in particular to medicines and preparations, as well as to methods for their preparation. More specifically, the invention relates to parenteral drugs with improved pharmacological parameters, in particular, better solubility in aqueous media, improved bioavailability of the active substance, reduced toxicity, prolonged action, etc.

Among drugs, there are many substances that, due to their chemical nature, have poor pharmacological properties, for example, have low solubility in water (lipophilic compounds) and low bioavailability, exhibit significant toxicity, are rapidly excreted from the body, which leads to the need for frequent administration or injection of the drug to maintain the concentration of the active substance at a therapeutic level, and, as a result, to increase the likelihood of side effects etc. All this together imposes a number of restrictions on the use of such drugs by patients [Mashkovsky M.D. Medicines M .: "New Wave", 2005, 1200 p .; Kharkevich D.A. Pharmacology. M .: "Geotar Medicine", 2006, 736 p .; Register of medicines of Russia. Encyclopedia of drugs. 15th edition. M .: "Radar-2007", 2006. 1488 p.]. In this regard, the development of drugs with improved pharmacological parameters, allowing to achieve higher efficiency with medical use, is an urgent task.

For example, a parenteral drug and a method for producing such a drug in the form of a biodegradable composition having a sustained release of a biologically active compound are known [RF Patent 2290950, 2007]. This technical solution involves overcoming the removal of the medicine from the body too quickly. The drug consists of a biodegradable carrier, which is a product of high-temperature (120-220 ° C) polycondensation of polyhydric alcohol (in particular glycerol, pentaerythritol, mannitol, sorbitol) and aliphatic alpha hydroxy acid (for example, DL-lactic, glycolic, alpha hydroxybutyric, etc.), with a molar ratio of comonomers from 0.5: 99.5 to 12:88; in addition, the composition includes an active substance selected from anti-inflammatory non-steroidal, antimicrobial, antitumor and other agents, as well as a liquid plasticizer (tributyl citrate, tributyrin, triethyl citrate, etc.), which is introduced in a mass ratio with the carrier from 1:20 to 9:10 . The method of obtaining this composition involves intensive mixing of the carrier, plasticizer and active substance at temperatures up to 75 ° C with the formation of a homogeneous mixture. Such a mixture is packaged in ampoules, followed by sterilization with gamma radiation and stored in the refrigerator. Biotesting in mice of a drug containing cisplatin as the active substance and obtained according to this technical solution shows an improvement in the therapeutic effect (decrease in growth rate and tumor mass), and also detects the effect of prolonged release of the antitumor agent. The disadvantages of this technical solution include undesirable processes that occur at high temperatures during the preparation of both the polymer carrier and the final composition, which significantly increases the risk of the formation of thermal degradation products of the components of the composition, some of which may be toxic to users. In addition, the drug must be heated to 50 ° C before intratumoral administration, which makes it unsuitable for human therapy.

Significantly milder conditions are known for the preparation of such a potential drug as the stabilized form of the dinitrosyl iron complex (DNIC) [RF Patent 2291880, 2007]. This stable form of DNIC has a pronounced hypotensive effect with parenteral administration. According to this technical solution, the method of obtaining the specified form consists in mixing the components of the composition (DNIC 0.1-6.0 wt.%; Polymer stabilizer 1-20 wt.%; Water up to 100 wt.%), Freeze the resulting composition at -10 ... -196 ° C for 0.1-24 hours and freeze-dried to a residual moisture content of 0.1-2.0%. In vivo testing in rats reveals the same absolute effects of lowering blood pressure both in the case of freshly prepared DNIC, which is stable for no more than 30 minutes at room temperature, and in the case of a stabilized polymer form of DNIC that was stored at + 25 ° C for two months, but the effect of the latter is manifested over a longer (2-3 times) time, i.e. a pronounced prolonging effect takes place. However, this known technical solution is applicable only to medicinal substances that are readily soluble in water, i.e. is not universal enough. In the case of lipophilic drug substances, the corresponding composition cannot be obtained in this way, since either coagulation of the polymer stabilizer or uncontrolled deposition of the lipophilic component is observed.

An example of a solution to the problem of low solubility of lipophilic drug substances is a well-known drug containing an active substance that is poorly soluble in water (for example, paclitaxel, teniposide, etc.) and a solubilizing agent, which is a mixture (50:50 by volume) of absolute ethanol and non-polymer additives - polyoxyethylated castor oil (so-called Cremafor EL) [US Patent 5504102, 1996]. This technical solution allows to obtain fairly stable solutions of lipophilic substances that are acceptable for parenteral use. The disadvantages of this drug include the presence of Cremaphore EL in its composition, which leads to the extraction of di (2-hexyl) phthalate - a plasticizer in polyvinyl chloride (PVC) products used in biomedical equipment. As a result, di (2-hexyl) phthalate harmful to humans is solubilized and enters the patient's body. In addition, according to the data of the RF Patent 2291693 (2007), polyoxyethylated castor oil when administered parenterally into the human body can have side effects, for example, increase blood pressure, cause shortness of breath, lead to nervous exhaustion, etc.

One of the determining pharmacological parameters of drugs is their toxicity, and this problem is especially relevant for anticancer pharmaceuticals, many of which are extremely toxic and, along with cancerous cells, also affect healthy cells. So, for example, a parenteral antitumor drug based on a substance of plant origin - paclitaxel is known. This drug is a nanoparticle formed from human serum albumin with paclitaxel incorporated therein [US Patent 5916596, 1999] with an albumin / pharmacological agent ratio of 9: 1 parts by weight. Such a drug is obtained by adding a solution of paclitaxel in methylene chloride or chloroform to an aqueous solution of human serum albumin, followed by homogenization of the mixture under excessive pressure. Next, the organic solvent from the resulting emulsion is removed on a rotary evaporator, and the residue is frozen and freeze-dried. Biotesting [US Patent 6537579, 2003] of the drug thus obtained in mice and rats shows a significant decrease in toxicity (up to 10 times) compared with the drug known under the trade name Tachol (527 wt. Per 6 parts by weight of paclitaxel parts by weight of Cremaphore EL and 400 parts by weight of absolute ethanol).

This technical solution [US Patent 5916596, 1999], as the closest to the claimed in a set of components, including a pharmacological agent, a water-soluble polymer and a solvent, was chosen by us for the prototype.

However, the prototype has several disadvantages:

- solvents that are toxic to internal organs of the person (in particular, to the liver) are used — organochlorine liquids that are well adsorbed by various polymers. The method used in the prototype method (evacuation on a rotary evaporator) does not ensure the complete removal of methylene chloride or chloroform, especially from an adsorption-bound polymer (albumin) state;

- when emulsifying an organic solution of paclitaxel in an aqueous solution of albumin at the interface between the aqueous and organic phases, protein denaturation occurs due to non-specific hydrophobic interactions, i.e. some of the albumin molecules lose their native conformation, which undesirably affects the immunogenicity of albumin, and this, in turn, can cause a severe allergic reaction in patients with reduced immunity, for example in cancer patients;

- the method of obtaining the final drug requires complex hardware design process due to the need to work with high pressure at the stage of emulsification;

- when implementing the known method produces harmful to the environment waste - waste organochlorine solvent.

The inventors of the present invention provide a new pharmaceutical composition for a parenteral drug and a method for its preparation.

The following are definitions and abbreviations used in the description of the invention.

A medicinal product is a substance or mixture of substances intended for the treatment and prevention of diseases.

Pharmacological agent - a substance with pharmacological activity and used as the main ingredient of the drug.

A non-covalent complex is a complex that is formed between molecules of substances in a suitable solvent due to intermolecular interactions of a non-covalent nature, namely, hydrogen bonding, coordination-ionic, and also hydrophobic interactions.

Residual solvent - a solvent that remains an adsorption-bound non-covalent complex after drying of its solution by the method used.

Pharmacological agent

I - ampicillin

II - bleomycin

III - diphenhydramine

IV - dobutamine

V - dopamine

VI - docetaxel

VII - lanreotide

VIII - octreotide

IX - paclitaxel

X - cefazolin sodium salt

XI - ethylmethylhydroxypyridine succinate

XII - Zidovudine

Water soluble polymer

A - human serum albumin

B - 2-hydroxyethyl starch

C - dextran

D - Gelatin

E - Poly (N-vinylpyrrolidone)

F - mixture

Non-polymer additive

α - (C ₁₀ -C ₁₈ ) acyl sorbitol

β - oligooxyethylene (C ₁₀ -C ₁₈ ) acyl sorbitol

γ - (C ₁₀ -C ₁₈ ) Oligoethylene glycol alkyl ether

Solvent

a - water

b - dimethyl sulfoxide

c - N-methyl-2-pyrrolidone

g - 2-pyrrolidone

d - ethanol

** Drying Method:

LS - freeze drying

PC - spray drying

UP - evaporation in vacuum

*** Solubility:

low - less than 1 g / l

wednesday - 1-10 g / l

the choir. - 10-100 g / l

high - more than 100 g / l

**** in rel. units from standard (LD ₅₀ )

n / a - not determined

The technical result of the present invention is to create a new pharmaceutical composition for producing a parenteral drug having a set of improved pharmacological parameters, such as toxicity, duration of exposure, bioavailability, and method for its preparation.

The technical result is achieved in that the pharmaceutical composition for the preparation of a parenteral medicinal product includes a pharmacological agent, a water-soluble polymer, a non-polymer additive and a residual solvent, where the water-soluble polymer is selected from the group: dextran, gelatin, 2-hydroxyethyl starch, poly (N-vinylpyrrolidone), serum albumin human blood or a mixture thereof; the non-polymer additive is selected from the group: (C ₁₀ -C ₁₈ ) acyl-sorbitol, oligooxyethylene (C ₁₀ -C ₁₈ ) acyl-sorbitol, (C ₁₀ -C ₁₈ ) oligoethylene glycol alkyl ether, the pharmacological agent, water-soluble polymer, non-polymer additive and the residual solvent is included in the pharmaceutical composition in the form of a non-covalent complex in the following ratio (parts by weight): pharmacological agent 0.10-100, water-soluble polymer 1-100, non-polymer additive 0.001-100, residual solvent 0.3-30.

The technical result is also achieved by the fact that the method of obtaining the pharmaceutical composition consists in preparing the composition by mixing a pharmacological agent, a water-soluble polymer and an unpolymer additive with a solvent in the following proportions (parts by weight):

pharmacological agent 0.10-100; water soluble polymer 1-100; non-polymer additive 0.001-100; solvent 10-200,

moreover, the solvent is a mixture of water with ethanol, or dimethyl sulfoxide, or N-methyl-2-pyrrolidone, or 2-pyrrolidone in a volume ratio of from 99.9: 0.1 to 50:50, followed by drying of the composition to a residual solvent 0.3-30 parts by weight

The technical result is also achieved by the fact that the parenteral drug for the treatment and prevention of diseases of the nervous system, or diseases of the cardiovascular system, or cancer, or viral diseases, or infectious diseases, includes the above pharmaceutical composition.

The choice of components and the quantitative composition of the claimed pharmaceutical composition, as well as the parameters of the method for its preparation, is due to the following factors.

1) The solvent used must be approved for medical use and allow the preparation of solutions of the components of the composition upon receipt of a non-covalent complex; It is proposed to use as such a solvent a mixture of water with ethanol, or dimethyl sulfoxide, or N-methyl-2-pyrrolidone, or 2-pyrrolidone in a volume ratio of

99.9: 0.1 to 50:50.

2) Components of the claimed pharmaceutical composition, i.e. a pharmacological agent, a water-soluble polymer and a non-polymeric additive are included in the form of a non-covalent complex, which provides a prolonged effect with respect to the action of the pharmacological agent, the chemical structure of which does not change, but for the dissociation of such a non-covalent complex, a certain additional time is required, depending on the individual properties of the components of the drug. In the preparation of the claimed pharmaceutical composition, a pharmacological agent, a water-soluble polymer and a non-polymer additive are selected so that in the above common solvent they can form a non-covalent complex due to intermolecular interactions of non-covalent nature: hydrogen bonding, coordination-ionic, as well as hydrophobic interactions. This approach, on the one hand, ensures the invariability of the chemical structure of the pharmacological agent, therefore, does not affect the nature of the physiological activity exhibited by it, and on the other hand, the non-polymer additive and the water-soluble polymer perform a solubilizing function, thereby, along with a prolonging effect, provide better solubility in an aqueous environment of a pharmacological agent, and, as a consequence, increased bioavailability. In some cases (see examples of the implementation of the claimed technical solution), along with the above effects, a decrease in the toxicity of the drug is observed, i.e. in general, there is a noticeable comprehensive (multifactorial) improvement in the pharmacological parameters of the resulting parenteral drug in comparison with analogues and prototype.

3) The choice of specific representatives of the pharmacological agent is due to relatively low pharmacological parameters, for example, insufficient solubility in aqueous media, low bioavailability, increased toxicity, too fast excretion from the body, etc. However, substances with good pharmacological properties can also be used as a pharmacological agent in the claimed invention. indicators, since the claimed technical solution can provide their further improvement. The present invention provides for the use of a pharmacological agent intended for the treatment and prevention of diseases of the nervous system, or diseases of the cardiovascular system, or cancer, or viral diseases, or infectious diseases.

4) In the present invention, the choice of a water-soluble polymer and a non-polymer additive is determined, on the one hand, by their chemical nature, which determines the possibility of the formation of a non-covalent complex with a specific pharmacological agent, and, on the other hand, by their accessibility, harmlessness when administered parenterally, and their properties unchanged for long storage, etc. The claimed technical solution provides for the use of natural and synthetic compounds such as dextran, gelatin, 2-hydroxyethyl starch, poly (N-vinylpyrrolidone), human serum albumin and mixtures thereof as a water-soluble polymer, and (C ₁₀ -C ₁₈ ) acyl sorbitol, oligooxyethylene (C ₁₀ -C ₁₈ ) acyl sorbitol, (C ₁₀ -C ₁₈ ) alkyl ether of oligoethylene glycol.

5) The quantitative composition of the claimed pharmaceutical composition was found experimentally and was determined as the necessary therapeutic dose for a particular pharmacological agent, and technological features of the implementation of the proposed method, for example, the solubility of the components of the composition in the preparation of the non-covalent complex “pharmacological agent-water-soluble polymer - non-polymer additive”. According to the proposed technical solution, the solvent is included in the amount of 10-200 parts by weight, and the remaining components in an amount: 0.10-100 parts by weight. (pharmacological agent), 1-100 parts by weight (water soluble polymer) and 0.001-100 parts by weight (non-polymer additive).

b) When implementing a method for producing a pharmaceutical composition for a parenteral drug having improved pharmacological parameters, a composition of the claimed composition is first prepared, which is then dried. Drying is carried out by known methods, for example, by evaporation, spray drying or freeze drying, which is determined by the properties (in particular, heat resistance) of a particular pharmacological agent, as well as the volatility of the solvent used and, finally, the economic parameters of the selected drying method. The inventive range of residual solvent in the resulting parenteral drug is determined experimentally and is in the range of 0.3-30 wt.h. Getting the drug with less than 0.3 wt.h. the content of residual solvent is in principle possible, but this requires prolonged evacuation and often at elevated temperatures, which leads to unjustified excessive energy consumption. On the other hand, higher than 30 parts by weight the residual solvent content in the drug obtained according to the invention is undesirable because of the danger of microflora development, as well as the soaking of the drug in case of increased hygroscopicity of its ingredients.

The invention is illustrated by the drawing: the drawing shows the IR spectra of cefazolin sodium salt (2), dextran (1), a mechanical mixture of cefazolin sodium salt, dextran and dodecyl sorbitol (3), as well as the non-covalent complex "cefazolin sodium salt - dextran - dodecyl sorbitol " (four).

The following is an example implementation of the claimed invention, which illustrates, but does not limit its scope.

Example 1

In 10 parts by weight solvent containing 99.9 vol. including water and 0.1 vol. including ethanol, dissolve 0.5 wt.h. cefazolin sodium salt and 1 wt.h. dextran. Next, to the resulting solution add 0.001 wt.h. dodecyl sorbitol (α (C ₁₂ ) - in the designation of the table). This solution is frozen and freeze-dried (freeze drying) to a residual solvent content of ~ 0.3 wt.h. (determined by titration according to the method of C. Fisher). IR spectroscopic studies (see the drawing) confirm the formation of the non-covalent complex “cefazolin-dextran-dodecyl-sorbitol” due to hydrogen bonds: if the spectrum of the mechanical mixture (curve 3) contains all characteristic absorption bands, in particular a clear band at 3284 cm ^-1 stretching vibrations of NH bonds of amide groups of cefazolin sodium salt (curve 2), then this band is not explicitly present in the IR spectrum of the corresponding non-covalent complex (curve 4), but there is a “shoulder” of a wide band at 3300-3400 cm ^-1 corresponding to to Lebannen H-bonded NH-fragments.

The method of analytical ultracentrifugation shows that the hydrodynamic radius of the particles of the parenteral drug in water does not exceed 100 nm.

The pharmacological parameters of the obtained parenteral drug are determined on mice weighing about 30 g. A pure pharmacological agent is used as a control sample. The number of animals in each group is 8 individuals. The drugs are administered intraperitoneally in physiological saline in a dose (calculated as a pharmacological agent) of 20 mg / kg. Blood samples of animals are taken after 5, 15, 30, 60, 120 and 240 minutes and sample preparation is carried out according to standard methods. The concentration of the active substance in the samples is determined using chromatography-mass spectrometry. An analysis of the results of in vivo testing of a parenteral drug prepared according to the claimed technical solution shows that, compared with the control sample, an increase in bioavailability (by 20%) and an increase (1.9 times) in the half-life (T _1/2 ) of the pharmacological agent, i.e. a significant prolongation effect is detected. Thus, in this case (example 1.2), the claimed drug has pronounced improved pharmacological parameters, due to the combination of features of the proposed technical solution, namely, the pharmacological agent is part of the drug in the form of a non-covalent complex with a water-soluble polymer and non-polymer additive.

The present invention has the following advantages compared with analogues and prototype.

1) The claimed technical solution is characterized by a high degree of versatility with respect to the possibility of obtaining parenteral drugs with improved pharmacological parameters based on a wide variety of pharmacological agents intended for the treatment and prevention of diseases of the nervous system (example numbers in table 4.2, 11.2) or diseases of the cardiovascular system (5.2, 8.2), or cancer (3.2, 6.2, 6.3, 7.2, 7.3, 9.2, 9.3, 10.2), or viral diseases (12.2), or infectious diseases (1.2, 2 .2, 2.3). In particular, the data of columns 13-16 of the table of examples show a significant improvement in pharmacological parameters in representatives of similar drugs, which confirms the universality of the invention.

2) The achieved effect of improving the pharmacological parameters of the claimed parenteral medicinal product is synergistic, i.e., as a rule, there is an improvement not just of one specific pharmacological indicator, but of a whole set of such indicators (examples of numbers in table 2.2, 2.3, 3.2, 6.2, 6.3, 7.2, 7.3, 9.2, 9.3, 10.2, 12.2). In addition to the main function that determines the role of a water-soluble polymer in the claimed technical solution (complex improvement of pharmacological parameters), this component of the non-covalent complex can simultaneously perform such additional functions as, for example, binding and excretion of undesirable substances such as organic toxicants from the body using poly (N -vinylpyrrolidone), albumin, 2-hydroxyethyl starch or dextran.

3) One of the principal advantages of the present invention relates to a significant increase in water solubility of lipophilic pharmacological agents (example numbers in table 2.2, 2.3, 6.2, 6.3, 7.2, 7.3, 9.2, 9.3,10.2), which increases their bioavailability and as a result allows reduce the applied therapeutic dose, and this is especially important for substances with severe toxicity, in particular antitumor agents.

4) When implementing the proposed technical solution, the use of toxic chlorine-containing organic solvents is excluded. Moreover, after preparing a solution of the components of the composition, this solution is then dried, therefore, a small amount of the solvent that remains adsorption-bound in the resulting preparation is not dangerous and all the more toxic for patients taking such a drug, which is confirmed by biotesting data, namely, a decrease in toxicity the claimed drugs in comparison with the pharmacological agent (the numbers of examples in table 3.2, 6.2, 6.3, 7.2, 7.3, 9.2, 9.3, 10.2, 12.2).

5) The proposed method for producing a pharmaceutical composition, which is part of a parenteral drug with improved pharmacological parameters, unlike analogues and prototype, involves the use of standard equipment for pharmaceutical production, i.e. characterized by good adaptability. Also, the claimed invention is based on the use of very mild modes of all technological stages, which ensures the preservation of the physiological activity of the active substance in the composition of the resulting drug.

Claims (2)

1. A pharmaceutical composition for the production of a parenteral drug, comprising a pharmacological agent, a water-soluble polymer, a non-polymer additive and a residual solvent, characterized in that the water-soluble polymer is selected from the group: dextran, gelatin, 2-hydroxyethyl starch, poly (N-vinylpyrrolidone), serum albumin human blood or a mixture thereof; the non-polymer additive is selected from the group: (C ₁₀ -C ₁₈ ) acyl-sorbitol, oligooxyethylene- (C ₁₀ -C ₁₈ ) acyl-sorbitol, (C ₁₀ -C ₁₈ ) oligoethylene glycol alkyl ether, the pharmacological agent, water-soluble polymer, non-polymer additive and the residual solvent is included in the composition in the form of a non-covalent complex in the following ratio, parts by weight: pharmacological agent 0.10-100, water-soluble polymer 1-100, non-polymer additive 0.001-100, residual solvent 0.3-30. 2. The method of obtaining the pharmaceutical composition according to claim 1, which consists in preparing the composition by mixing a pharmacological agent, a water-soluble polymer and a non-polymer additive with a solvent in the following proportions, parts by weight:
pharmacological agent 0.10-100 water soluble polymer 1-100 non-polymer additive 0.001-100 solvent 10-200
moreover, the solvent is a mixture of water with ethanol, or dimethyl sulfoxide, or N-methyl-2-pyrrolidone, or 2-pyrrolidone in a volume ratio of 99.9: 0.1 to 50:50, followed by drying of the composition to a residual solvent of 0 3-30 parts by weight

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