阅读说明：本技术 基于吲哚美辛薄荷酯的药物组合物及其作为抗炎剂的用途 (Pharmaceutical compositions based on indomethacin menthyl esters and their use as anti-inflammatory agents ) 是由 约瑟夫·施瓦兹 迈克尔·威斯帕 娜塔莉亚·安娜托里耶夫娜·施米科娃 谢尔盖·阿列克山德罗维奇· 于 2018-12-27 设计创作，主要内容包括：本发明涉及基于吲哚美辛薄荷酯的药物组合物,其可用作抗炎药以治疗急性和慢性炎性疾病。上述药物组合物具有抗炎、镇痛和解热作用,并且在治疗剂量下没有不良致溃疡作用。(The present invention relates to pharmaceutical compositions based on indomethacin menthyl ester, which are useful as anti-inflammatory agents for the treatment of acute and chronic inflammatory diseases. The pharmaceutical composition has anti-inflammatory, analgesic and antipyretic effects, and has no adverse ulcer-inducing effect at therapeutic dose.)

1. Use of an indomethacin menthyl ester based pharmaceutical composition with anti-inflammatory, analgesic and antipyretic effects comprising 5-methyl-2- (propan-2-yl) cyclohexan-1-yl ] { [ 2-methyl-5-methoxy-7- (4-chlorobenzoyl) -1H-indol-3-yl ] acetate } and a pharmaceutically acceptable excipient as an anti-inflammatory agent for the treatment of acute and chronic inflammatory diseases by enteral (including oral and rectal) or parenteral (including by injection or application to the skin) administration to a mammal to ensure the bioavailability of indomethacin menthyl ester.

Technical Field

The present invention relates to drugs and anti-inflammatory agents, in particular to pharmaceutical compositions based on indomethacin esters, which can be used for the treatment of acute and chronic inflammatory diseases.

Background

The closest compound to the disclosed compounds (i.e. the prototype of the invention) is indomethacin (1- (4-chlorobenzoyl) -5-methoxy-2-methyl-1H-indole-3-acetic acid), a well-known non-steroidal anti-inflammatory drug (NSAID), which exerts potent anti-inflammatory, analgesic and antipyretic effects. Indomethacin in the form of capsules, tablets, suppositories, injections and other systemically acting dosage forms is widely used in the treatment of arthritis and other inflammatory and degenerative diseases of the musculoskeletal system, in the treatment of pain of different origins, in the combined treatment of some infectious-inflammatory and neoplastic diseases.

Indomethacin, however, is highly toxic (L D50 administered orally to rats is less than 15mg/kg) and induces severe adverse effects in systemic use, hi particular, indomethacin exerts a so-called ulcerogenic effect, severely stimulates the mucosa of the gastrointestinal (GI tract) organs, causing ulceration and dangerous bleeding, this ulcerogenic effect is directly related to the mechanism of action of indomethacin and other NSAIDs, indomethacin is an inhibitor of two forms of cyclooxygenase (COX-1 and COX-2) which is responsible for the synthesis of prostaglandins, and when indomethacin reaches a certain concentration in the blood, the synthesis of prostaglandins is destroyed both in the site of inflammation and in the gastric mucosa, leading to erosions and ulcerations.

Different indomethacin derivatives were studied to reduce the gastrointestinal toxicity of indomethacin. Different esters, amides, Mannich bases (Mannich bases) and some other hydrolysable compounds were synthesized. In some cases, such modifications reduce the ulcerogenic effect or alter the selectivity of cyclooxygenase inhibition [ 1; 2]. Patent [3] discloses the use of pharmaceutical compositions containing indomethacin Menthyl Ester (MEI) as ophthalmic drugs for topical use for the treatment of inflammatory eye diseases. The article [4] also describes the synthesis of several indomethacin derivatives, including their menthyl esters, and their use as NSAIDs. The efficacy of MEI is related to its hydrolysis in the organism and the production of free indomethacin with potent anti-inflammatory action. However, there are currently no systemically acting drugs based on indomethacin derivatives (including MEI) which combine high anti-inflammatory activity with safety in use (in particular low gastrointestinal toxicity). One reason for this is the relationship between the efficacy of the anti-inflammatory effect and the severity of the adverse ulcerogenic effect. In the case of MEI, there is a second problem-the bioavailability of this compound is low: unlike indomethacin, MEI is practically not absorbed in the gastrointestinal tract when administered orally. Therefore, in order to achieve systemic anti-inflammatory effects, it is necessary to develop specific pharmaceutical compositions that will ensure the bioavailability of MEI, achieving effective concentrations of indomethacin in the blood.

Disclosure of Invention

The aim of the present invention is to create a MEI-based pharmaceutical composition that will ensure the bioavailability and reach effective blood concentrations of indomethacin without (or with low severity of) adverse ulcerogenic effects, providing anti-inflammatory activity, which will allow the use of MEI-based pharmaceutical compositions as effective and safe NSAIDs with systemic effect.

This object is achieved by creating a MEI-based pharmaceutical composition that ensures high bioavailability and anti-inflammatory activity without adverse ulcerogenic effects. These pharmaceutical compositions comprise MEI (5-methyl-2- (propan-2-yl) cyclohexan-1-yl ] { [ 2-methyl-5-methoxy-7- (4-chlorobenzoyl) -1H-indol-3-yl ] acetate }) and different pharmaceutically acceptable excipients.

In one embodiment, the pharmaceutical composition comprises liposome-encapsulated MEIs (MEI-loaded liposomes). Lipids (preferably phospholipids such as lecithin, e.g. hydrogenated soy lecithin powder or liquid lecithin) are used as structure forming components of liposomes in order to produce liposome encapsulated MEIs. When lecithin is used, it is necessary to add a solubilizing agent, such as glycerol, ethanol or other pharmaceutically acceptable solubilizing agents. Pharmaceutically acceptable non-polar solvents (e.g., triglycerides, including medium chain triglycerides of caprylic and capric acids) are used as solvents (molecular carriers) for MEIs. To prepare MEI-loaded liposomes, hydrophobic antioxidants (such as ascorbyl palmitate), penetrants (such as maltodextrin) and other pharmaceutically acceptable ingredients (such as tocopheryl acetate, retinyl palmitate, red palm oil, coenzyme Q) and other ingredients necessary to produce stable pharmaceutical compositions based on liposome-encapsulated MEIs are added.

In other embodiments, the pharmaceutical composition is a solution or dispersion based on MEI and excipients: non-polar solvents such as mono-, di-and triglycerides of fatty acids and other pharmaceutically acceptable non-polar solvents; alcohols, water and other polar solvents; emulsifiers, surfactants such as lecithin, polysorbates, and other pharmaceutically acceptable excipients necessary to produce a stable dispersion or solution that will convert to a stable dispersion in aqueous and biological media.

The MEI-based pharmaceutical compositions may also be suppositories, e.g. rectal suppositories, using polyethylene glycol (such as PEG400, PEG (macrogol)1500, 4000 or 6000), or solid fats (triglycerides of fatty acids) (such as Witepsol or Supsuosyl) as the base for suppository formation.

The MEI-based pharmaceutical compositions may be included in dosage forms for enteral use (including for oral and rectal administration), or parenteral use (including administration to the skin and mucosa of an organism, or by injection (e.g., intravenous, subcutaneous, intramuscular, intraarticular injection) or other methods of ensuring systemic action), and also in dosage forms for topical use, in addition to eye drops and other ophthalmic compositions. MEI-based pharmaceutical compositions may be included in liquid dosage forms (including solutions, suspensions, and emulsions); soft dosage forms (including ointments); suppositories and patches; solid dosage forms (including tablets and capsules), as well as other dosage forms that ensure the delivery of MEI and its metabolite indomethacin to the site of inflammation for the treatment of acute and chronic inflammatory diseases.

The resulting MEI-based pharmaceutical compositions were studied using in vitro and in vivo models to evaluate their bioavailability and pharmacokinetic profiles in blood, and also to evaluate anti-inflammatory activity and adverse ulcerogenic effects.

Example 1

The following components (calculated as 1 therapeutic dose of MEI) were used to create pharmaceutical compositions based on emulsions of liposome-encapsulated MEI:

1) MEI substance (powder) -10 to 100 mg;

2) 60% -10 to 100mg of lecithin;

other ingredients in amounts necessary to produce a stable liposome emulsion, including:

3) 96% of ethanol;

4) a pharmaceutically acceptable glycerin;

5) maltodextrin powder;

6) carrageenan GS;

7) potassium sorbate;

8) sodium benzoate;

9) grindox antioxidant;

10) purified water.

Since MEI is lipophilic, MEI is bound to phospholipids by fusing it with a lecithin/MEI ratio of 0.5/1-10/1 (preferably a lecithin/MEI ratio of 2/1). At this ratio, the liposomes produced remain stable when stored in the gel, and high concentrations of active agent are achieved in the liposomal membrane and in the final liposomal gel formulation. The fusion temperature of lecithin and MEI substance was chosen based on the physical properties of MEI and was 75 ± 5 ℃. At this temperature, the mixture has the required fluidity and viscosity to produce the proliposomal bilayer, which subsequently closes on itself, producing spherical vesicles. In this process, the MEI is present in the melt in its molecular form, thus ensuring its homogeneous distribution in the liposome bilayer. Proliposomes are prepared by mixing a molten lecithin/MEI mixture with an ethanol-glycerol mixture in a ratio of 2/1 at a temperature of 25-55 deg.C (preferably 40 + -5 deg.C). The liposome emulsion is prepared at the same temperature as the proliposome (preferably at 40 + -5 deg.C) by homogenizing at a rate of 1000-10000RPM (preferably 2000-3000RPM) for 1-10 minutes (preferably 1-2 minutes). The liposome emulsion was stabilized by a carrageenan mixture (carrageenan GS) at a temperature of 75 ℃.