CN114870016B

CN114870016B - Micro-emulsion foaming agent of JAK inhibitor and application thereof

Info

Publication number: CN114870016B
Application number: CN202210423007.9A
Authority: CN
Inventors: 华丽; 谢军; 姜春阳; 李惠; 舒海英; 黄利明
Original assignee: Shanghai Scienpharm Biotechnology Co ltd
Current assignee: Shanghai Scienpharm Biotechnology Co ltd
Priority date: 2022-04-21
Filing date: 2022-04-21
Publication date: 2023-05-26
Anticipated expiration: 2042-04-21
Also published as: WO2023202580A1; CN114870016A

Abstract

The invention relates to a microemulsion foaming agent composition for treating alopecia areata, atopic dermatitis and leucoderma and a preparation method thereof. Has effects of caring skin and keeping moisture, and has no irritation to skin, no side effects such as itching, burning sensation and tingling sensation, and no related dermatoses symptoms after stopping administration.

Description

Micro-emulsion foaming agent of JAK inhibitor and application thereof

Technical Field

The invention belongs to the field of pharmaceutical preparations, and relates to a micro-emulsion foaming agent of a JAK inhibitor, a preparation method and application thereof.

Background

JAK inhibitors can selectively inhibit JAK kinase and block JAK/STAT signal paths, and are mainly used for screening therapeutic drugs such as blood system diseases, tumors, rheumatoid arthritis and psoriasis clinically. Janus kinases (JAK) are a family of intracellular non-receptor tyrosine kinases that transduce cytokine-mediated signals through the JAK-STAT pathway. Since members of the type I and type II cytokine receptor families do not possess catalytic kinase activity, they rely on the JAK tyrosine kinase family to phosphorylate and activate downstream proteins involved in their signal transduction pathways. The receptor exists as a mating polypeptide and thus exhibits two intracellular signaling domains. JAK is associated with a proline-rich region in each intracellular domain, adjacent to the cell membrane, called the box1/box2 region. Upon binding of the receptor to its respective cytokine/ligand, it undergoes a conformational change that brings the two JAKs close enough to phosphorylate each other. JAK autophosphorylation induces conformational changes in itself, enabling it to transduce intracellular signals by further phosphorylating and activating a transcription factor called STAT. Activated STATs dissociate from the receptor and form dimers where they regulate transcription of selected genes prior to transfer to the nucleus. JAK inhibitors include abxitinib, wu Pati, poncirtinib, baratinib, tofacitinib, SHR0302, jacktinib hydrochloride, and the like.

Ponatinib is a small molecule, an orally available Janus kinase subtype 1 and 2 (JAK 1 and JAK 2) specific inhibitor, approved in 2011 for use in the united states for the treatment of medium-high risk myelofibrosis. Subsequently, the indications expand to include polycythemia vera that is resistant or intolerant to conventional therapies and acute graft versus host disease that is resistant to corticosteroids.

Acetinib is a once-daily oral JAK1 inhibitor and also one of the members of the global pipeline of the psijak inhibitor, and acts by modulating a variety of cytokines associated with atopic dermatitis including the interleukins IL-4, IL-13, IL-31, IL-22 and Thymic Stromal Lymphopoietin (TSLP). Inhibition of JAK1 is thought to modulate a variety of cytokines involved in the pathophysiology of atopic dermatitis, including the interleukins IL-4, IL-13, IL-31, IL-22 and Thymic Stromal Lymphopoietin (TSLP) 2021 month 9, which is approved by the british drug and health care administration (MHRA) for the treatment of moderate to severe Atopic Dermatitis (AD) in adults and adolescents 12 years and older. This is the first approval of the drug administration by the acixitinib worldwide. Subsequently, the albuxitinib tablet is marketed in japan, korea, the european union and the united states. In addition, the medicine is also researched for various indications such as psoriasis, systemic lupus erythematosus and arthritis. Only tablet dosage forms exist.

The FDA approved incytte CORP at 21, 9, 2021, marketed as opzelu's rucotinib cream is approved for the short-term and discontinuous chronic treatment of mild to moderate AD in non-immunocompromised patients 12 years old and older. AD is a chronic skin disorder affecting persons older than 2100 tens of thousands of years 12 and older in the united states characterized by inflammation and itching, signs and symptoms including irritation and itching of the skin, which can lead to red lesions that may exude and scab, and patients are also more susceptible to bacterial, viral and fungal infections. The ponatinib cream can also be used for treating diseases such as atopic dermatitis, vitiligo and the like.

Compared with the cream, the microemulsion foam has the advantages of low skin retention, and can bring greasy feeling to patients, has good stability, spreadability and easy application, is particularly suitable for hair skin, is easier to use and does not adhere to hair, has higher skin penetration and skin retention than the cream, can provide non-greasy feeling to patients after use, does not stain clothes, and is simple and convenient in clinical use. There is therefore a need to develop a novel JAK inhibitor microemulsion foam.

Disclosure of Invention

The invention aims to overcome the defects of the JAK inhibitor emulsifiable paste and provides a micro-emulsion foaming agent of a JAK inhibitor, a preparation method and application thereof.

The aim of the invention is realized by the following technical scheme:

the invention relates to a microemulsion foam agent of a JAK inhibitor, which is characterized by comprising a therapeutically effective amount of a JAK inhibitor and auxiliary materials, wherein the auxiliary materials comprise an oil-in-water surfactant (foaming type), a cosurfactant, an oil phase, a humectant or solvent, an emollient, a chelating agent and a preservative.

As one embodiment, the present invention relates to a microemulsion foam formulation of a JAK inhibitor, the JAK inhibitor active ingredient being a therapeutically effective dose of a JAK inhibitor, preferably 0.5% -3% of a JAK inhibitor active ingredient selected from any one or more of albedinib, wu Pati, pontine, baritinib, tofacitinib, SHR0302, molotinib, jacktinib hydrochloride.

The JAK inhibitor microemulsion foam is a solution or suspension type oil-in-water preparation, contains 2-25% of oil-in-water surfactant, preferably 15-25% of cosurfactant, and contains 1-10% of cosurfactant, preferably 2-8%. Oil phase 0.2-1%, preferably 0.5-0.9%, chelating agent 0.01-1%, preferably 0.5-0.8%, humectant or solvent 4-25%, preferably 5-20%, emollient 0.5-2%, preferably 0.5-1%, preservative 0.1-1.0%, preferably 0.2-0.9%.

As one embodiment, the ratio of oil-in-water surfactant to co-surfactant is 6:1 to 3:1.

the oil-in-water surfactant is selected from one or more of caprylic acid capric acid polyethylene glycol glyceride, cetostearyl alcohol polyoxyethylene ether-20 and laurinol polyoxyethylene ether, preferably one or two of caprylic acid capric acid polyethylene glycol glyceride or cetostearyl alcohol polyoxyethylene ether-20.

Cosurfactants are surfactants that act by further lowering the interfacial energy in addition to surfactants, but do not act effectively as surfactants alone. The cosurfactant is selected from one or more of polyglycerol fatty acid ester, propylene glycol fatty acid ester, glyceryl monostearate, diethylene glycol monoethyl ether, polyglycerol 3-oleate, etc., preferably one or two of polyglycerol fatty acid ester, propylene glycol fatty acid ester, diethylene glycol monoethyl ether.

The oil phase is selected from medium chain triglyceride, cyclomethicone, isopropyl palmitate, triacetin light liquid paraffin, etc., preferably any one or more of medium chain triglyceride, cyclomethicone and isopropyl palmitate.

The chelation is selected from any one of disodium ethylenediamine tetraacetate, calcium disodium ethylenediamine tetraacetate and the like, and preferably disodium ethylenediamine tetraacetate.

The humectant or solvent is selected from one or more of propylene glycol, glycerol, polyethylene glycol-200, etc., preferably one or two of propylene glycol and polyethylene glycol-200.

The emollient is selected from one or more of propylene glycol dipelargonate, polydimethylsiloxane 350 and polyethylene glycol-7 cocoglyceride, preferably one or two of propylene glycol dipelargonate and polydimethylsiloxane 350.

The preservative is one or more of phenoxyethanol, propyl parahydroxybenzoate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, etc., preferably phenoxyethanol, propyl parahydroxybenzoate, methyl parahydroxybenzoate.

As one embodiment, the present invention relates to a JAK inhibitor microemulsion foam, wherein the raw materials and the prescription ratio (based on the total weight of the JAK inhibitor microemulsion foam) are as follows:

the invention also relates to a preparation method of the JAK inhibitor microemulsion foaming agent, which comprises the following steps:

(1) The preparation of active phase, dissolving the prescribed amount of active ingredient in humectant or solvent at 30-80deg.C, adding cosurfactant, and cooling to room temperature.

(2) Preparing an oil phase: at 30-80deg.C, stirring and dissolving O/W emulsifier, oil phase, chelating agent, antiseptic, and emollient, and cooling to room temperature.

(3) Adding the active phase into the oil phase, and stirring uniformly.

(4) And (3) adding the water into the mixture at room temperature, stirring the mixture uniformly, and regulating the pH value by using hydrochloric acid/sodium hydroxide to obtain the microemulsion foaming agent.

The invention also relates to application of the micro-emulsion foaming agent of the JAK inhibitor in external medicines for treating alopecia areata, atopic dermatitis, vitiligo and the like.

Compared with the prior art, the invention has the following beneficial effects:

microemulsion foams containing JAK inhibitors, i.e., compositions of microemulsion foams, are devoid of boosting agents and spontaneously form oil-in-water microemulsions when aqueous/oil-in-water surfactants/co-surfactants, oil phases, humectants or solvents, emollients, chelating agents, preservatives are mixed together at appropriate concentrations. The microemulsions formed are transparent to milky, optically isotropic and thermodynamically stable. The microemulsion can improve drug solubility, reduce skin irritation, and maintain internal phase and external phase concentration difference of drug to promote continuous permeation of drug through stratum corneum. The microemulsion foaming agent can spray foam through a specific drug delivery device without a booster, has good spreadability, is easy to apply, has good patient compliance, is particularly convenient for use on hair-containing skin, and has higher skin retention and penetration.

Drawings

Other features, objects and advantages of the present invention will become more apparent upon reading of the detailed description of non-limiting embodiments, given with reference to the accompanying drawings in which:

FIG. 1 foaming of example 1 microemulsion foam;

FIG. 2 foaming of example 2 microemulsion foam;

FIG. 3 example 3 foaming of a microemulsion foam;

FIG. 4 foaming of the microemulsion foam of example 4;

FIG. 5 example 5 foaming of microemulsion foam

FIG. 6 is a graph of foaming of the microemulsion foam of comparative example 2.

Detailed Description

The present invention will be described in detail with reference to examples. The following examples will assist those skilled in the art in further understanding the present invention, but are not intended to limit the invention in any way. It should be noted that several modifications and improvements can be made by those skilled in the art without departing from the inventive concept. These are all within the scope of the present invention.

The preparation method of the JAK inhibitor microemulsion foaming agent comprises the following steps:

(1) Preparation of active phase: dissolving the active ingredients in the prescription amount in propylene glycol solvent, adding cosurfactant, stirring at 30-50deg.C for dissolving, and cooling to room temperature.

(2) Preparation of an oil phase: stirring O/W emulsifier, oil phase, chelating agent, antiseptic, and emollient, heating to 30-50deg.C, dissolving, mixing, and cooling to room temperature.

(3) Adding the mixed oil phase into the water phase, stirring uniformly, and regulating the pH to 2.8-5.0 by using hydrochloric acid/sodium hydroxide to obtain the microemulsion foaming agent.

Specific examples of applications are as follows:

examples 1 to 4

The present examples 1-4 relate to the preparation of a ponteib microemulsion foam agent, wherein the raw materials and the auxiliary materials and the ratio are shown in the following table 1:

TABLE 1

Example 5

This example relates to the preparation of an abb-cipb microemulsion foam.

A microemulsion foam containing 1% of abb was prepared according to the formulation of table 2 and the preparation methods of examples 1-4.

TABLE 2

	Example 5
		Name of the name	Proportion of
Albumitinib	1
		Caprylic capric polyethylene glycol glyceride	20
Polyglycerol fatty acid ester	4
		Medium chain triglycerides	0.5
Polydimethylsiloxane 350	0.5
		Propylene glycol	22
EDTA-2Na	0.05
		Phenoxyethanol	0.5
P-hydroxybenzoic acid methyl ester	0.1
		Propyl p-hydroxybenzoate	0.05
Hydrochloric acid/sodium hydroxide	Proper amount of
		Water and its preparation method	51.3
Qs	100

Comparative example 1 preparation of control formulation

A cream containing pontinib was prepared as a control formulation according to the formulation of paragraph 0274 of page 19 of CN105853356a table 5 and the preparation process of paragraphs 0277-0286. The raw materials and the auxiliary materials and the ratio are shown in the following table 3.

TABLE 3 Table 3

Comparative example 2

This comparative example relates to the preparation of a ponatinib microemulsion foam, the raw materials and the ratio of which are shown in table 4 below, the preparation method is the same as that of example 2, but the adopted surfactant is different.

TABLE 4 Table 4

Name of the name	Proportion of	Adjuvant effect
			Pocotinib phosphate	1.98	API
Tween 60	20	O/w surfactant
			Polyglycerol fatty acid ester	4	Cosurfactant
Medium chain triglycerides	0.5	Oil phase
			Polydimethylsiloxane 350	0.5	Emollient(s)
Propylene glycol	15	Humectant and solvent
			EDTA-2Na	0.05	Chelating agent
Phenoxyethanol	0.5	Preservative agent
			P-hydroxybenzoic acid methyl ester	0.1	Preservative agent
Propyl p-hydroxybenzoate	0.05	Preservative agent
			Hydrochloric acid/sodium hydroxide	Proper amount of	PH regulator
Water and its preparation method	57.32	Solvent(s)
			Qs	100

EXAMPLE 6 quality comparison study

The viscosity, centrifugation, properties, droplet size, pH, content, related substances, content uniformity and the like were measured for examples 1 to 5 and comparative examples 1 to 2, and the results are shown in Table 5 below.

TABLE 5

Conclusion: foaming conditions of the tinib micro-emulsion foaming agents prepared in examples 1-5 and comparative example 2 are shown in figures 1-6. The microemulsion foams prepared according to examples 1 to 5 have good foaming ability, and comparative example 2 has poor foaming ability, and is easily changed into a solution without being smeared uniformly in clinical use, thereby causing the microemulsion to flow or drip from the skin surface.

The preparation of the pontine microemulsion foams according to examples 1-4 of this patent and the abzetinib microemulsion foam prepared in example 5 have good stability, spreadability, ease of application, and are easier to use and do not adhere to hair, especially for hair-bearing skin, than the cream of comparative example 1.

Example 7 results of Long term stability comparison study

Samples prepared in examples 1 to 4 and comparative examples 1 and 2 were placed at a temperature of 30.+ -. 2 ℃ and a humidity of 60.+ -. 5% RH, and the samples were sampled and tested for properties, viscosity, pH, content, and related substances for 1 month and 3 months, respectively, and the specific test results are shown in Table 6 below.

TABLE 6

From the comparative data of the long-term stability of example 7, the microemulsion foams prepared in examples 1 to 5 have good stability, and the properties, viscosity, pH, content and related material indexes have no significant change in the long-term period of three months. Illustrating that the microemulsion foams prepared according to examples 1-5 substantially meet stability requirements during use.

Example 8 in vitro transdermal test comparative study:

1) The method comprises the following steps: franz diffusion Chi Fa;

2) Instrument: LOGAN 918-12 system of transdermal diffusion tester for medicine

3) Skin: pigskin for experiments has a thickness of 0.8-1mm and a contact diameter of 2cm;

4) And (3) receiving liquid: physiological saline;

5) Receiving liquid temperature: 32+/-0.5 ℃;

6) Rotational speed: 600rpm;

7) Sample: the preparation of different prescriptions is uniformly coated on the pig skin for experiments, the sample size of each preparation is about 200mg, and simultaneously the pig skin without the cream is used as blank pig skin.

8) Diffusion Chi Rongji: 12ml;

9) Sampling mode: sampling all the materials;

10 Sampling time point): 2h, 4h, 6h, 10h, 21h, 24h;

11 Sample analysis: LC/MS measurement and detection results are shown in Table 7.

TABLE 7

As can be seen from the in vitro transdermal test of example 8, the prepared poncirtinib micro-emulsion foams of examples 1 to 4 have skin penetration and skin retention greater than those of the ointments, and the in vitro penetration test shows that they have better clinical effects than those of comparative examples 1 and 2. The microemulsion foam is an oil-in-water microemulsion foam which provides a non-greasy feel to the patient after use and does not stain clothes. The clinical use is simple and convenient.

The foregoing describes specific embodiments of the present invention. It is to be understood that the invention is not limited to the particular embodiments described above, and that various changes and modifications may be made by one skilled in the art within the scope of the claims without affecting the spirit of the invention.

Claims

1. The microemulsion foaming agent of the JAK inhibitor is characterized by comprising an active ingredient of the JAK inhibitor and auxiliary materials, wherein the auxiliary materials comprise an oil-in-water surfactant, a cosurfactant, an oil phase, a humectant or solvent, an emollient, a chelating agent and a preservative, and the oil-in-water surfactant is any one of caprylic-capric polyethylene glycol glyceride and cetostearyl alcohol polyoxyethylene ether-20; the cosurfactant is any one of polyglycerol fatty acid ester and propylene glycol fatty acid ester.

2. The microemulsion foam of JAK inhibitor according to claim 1, wherein the JAK inhibitor is selected from one or more of rucotinib phosphate, rucotinib, albocitinib, molotinib, and the active ingredient of the JAK inhibitor is 0.5% -3% by mass.

3. The JAK inhibitor microemulsion foam according to claim 1, wherein the auxiliary materials comprise, by mass, 2-25% of an oil-in-water surfactant, 1-10% of a cosurfactant, 0.2-1% of an oil phase, 0.01-1% of a chelating agent, 4-25% of a humectant or solvent, 0.5-2% of an emollient and 0.1-1.0% of a preservative, based on the total weight of the JAK inhibitor microemulsion foam.

4. The JAK inhibitor microemulsion foam according to claim 3, wherein the auxiliary materials comprise 15-25% of oil-in-water surfactant, 2-8% of cosurfactant, 0.5-0.9% of oil phase, 0.5-0.8% of chelating agent, 5-20% of humectant or solvent, 0.5-1% of emollient and 0.2-0.9% of preservative, based on the total weight of the JAK inhibitor microemulsion foam.

5. The microemulsion foam of a JAK inhibitor according to any one of claims 2 or 4, wherein the active ingredients and auxiliary materials of the JAK inhibitor are calculated according to the mass percent of the total weight of the microemulsion foam of the JAK inhibitor, and the ratio is as follows: 0.5-3% of poncirin phosphate, or acitinib or molotinib, 15-25% of caprylic/capric polyethylene glycol glyceride or cetostearyl alcohol polyoxyethylene ether, 2-8% of polyglycerin fatty acid ester or propylene glycol fatty acid ester, 0.5-0.9% of medium chain triglyceride, 0.5-1% of polydimethylsiloxane 350, 5-20% of propylene glycol, 0.5-0.8% of EDTA-2Na, 0.2-0.8% of phenoxyethanol, 0.05-0.15% of methyl parahydroxybenzoate, 0.01-0.1% of propyl parahydroxybenzoate, a proper amount of hydrochloric acid or sodium hydroxide, and water by a fixed weight of 100.

6. The microemulsion foam of a JAK inhibitor according to claim 1 having a ratio of oil-in-water surfactant to co-surfactant of 6:1 to 3:1.

7. the micro emulsion foam of the JAK inhibitor according to claim 1, wherein the oil phase is selected from any one of medium chain triglyceride, cyclomethicone, isopropyl palmitate and triacetin light liquid paraffin,

the humectant or solvent is selected from any one of propylene glycol, glycerol and polyethylene glycol-200,

the emollient is selected from any one of propylene glycol dipelargonate, polydimethylsiloxane 350 and polyethylene glycol-7 cocoglyceride.

8. A process for preparing a microemulsion foam of a JAK inhibitor according to claim 1, comprising the steps of:

a, preparation of an active phase: dissolving the prescribed amount of active ingredient in humectant or solvent at 30-80deg.C, adding cosurfactant, and cooling to room temperature;

b, oil phase preparation: stirring and dissolving the O/W emulsifier, oil phase, chelating agent, antiseptic and emollient in the prescribed amount at 30-80deg.C, and cooling to room temperature;

c, adding the active phase into the oil phase, and uniformly stirring;

d, adding the oil phase containing the active phase into water at room temperature, stirring uniformly, and regulating the pH value to obtain the micro-emulsion foaming agent.

9. The use of a microemulsion foam of a JAK inhibitor according to claim 1 in the preparation of a topical pharmaceutical formulation for the treatment of alopecia areata, atopic dermatitis, vitiligo.