WO2024114789A1

WO2024114789A1 - Pharmaceutical composition comprising trifarotene and use thereof

Info

Publication number: WO2024114789A1
Application number: PCT/CN2023/135836
Authority: WO
Inventors: 刘飞; 姜伟化; 康乐; 王旋; 王露露; 郑敏; 张翠霞
Original assignee: 南京迈诺威医药科技有限公司
Priority date: 2022-12-02
Filing date: 2023-12-01
Publication date: 2024-06-06
Also published as: CN118121532A

Abstract

A pharmaceutical composition comprising trifarotene, comprising trifarotene, a grease, an emulsifier, and water, wherein the grease is selected from at least one of caprylic capric triglyceride, caprylic triglyceride, isopropyl myristate, and mineral oil; the emulsifier is selected from at least one of sorbitan oleate and oleic acid polyethylene glycol glyceride. The addition of the emulsifier causes the composition to have a uniform texture and greatly improves the stability of trifarotene in the grease, thus effectively stabilizing the physical and chemical properties of the pharmaceutical composition, reducing irritation, and effectively improving the safety of drug use and the skin comfort.

Description

A pharmaceutical composition containing trefarotene and its application

This application claims the priority of the following prior application: Patent application number 202211543234.1 filed with the State Intellectual Property Office of China on December 2, 2022, and the invention name is “A pharmaceutical composition containing trefarotene and its application”. The entire text of the prior application is incorporated into this application by reference.

Technical Field

The invention belongs to the field of pharmaceutical compositions, and in particular relates to a topical pharmaceutical composition containing trefarotene and an application thereof.

Background technique

Trifarotene (Formula I) is a selective γ-retinoic acid receptor (RAR) agonist and keratolytic agent. In October 2019, the U.S. Food and Drug Administration (FDA) approved Galderma's Trifarotene Cream (trade name Aklief) for topical treatment of acne. This is the first retinoid molecule approved by the U.S. FDA for the treatment of facial and trunk acne, and belongs to the fourth generation of topical retinoid drugs.

Patent document CN 104507470 A discloses a topical composition of an oil-in-water emulsion type containing a retinoid, wherein the composition comprises a fat phase and an aqueous phase, wherein the fat phase comprises trefarotene, phenoxyethanol, one or more cosolvents and mineral oil, and the aqueous phase comprises at least one sucrose ester surfactant, at least one polyol and purified water. The emulsion has skin irritation, such as erythema, desquamation, skin burning sensation, dryness, itching and other skin adverse reactions.

Patent document CN 114848593 A discloses a foam composition comprising a retinoic acid drug, a surfactant and an aqueous solvent. The foam composition is mainly used for cosmetic purposes, has a short duration of action, and is difficult to exert the therapeutic effect of the drug.

Therefore, it is necessary to research and develop a topical preparation of trefarotene with low irritation, high skin comfort and wide skin applicability.

Summary of the invention

The purpose of the present invention is to overcome the above-mentioned defects and provide a pharmaceutical composition containing trefarotene which has good stability, low irritation and is comfortable to use.

In order to achieve the above object, the present invention provides the following technical solutions:

The first aspect of the present invention provides a pharmaceutical composition containing trefarotene, which comprises trefarotene, oil, emulsifier and water;

The oil is selected from at least one of caprylic capric triglyceride, caprylic triglyceride, isopropyl myristate, and mineral oil;

The emulsifier is selected from at least one of sorbitan oleate (Span 80) and oleic acid macrogol glyceride (Labrafil M 1944CS).

In some embodiments, the oil is selected from at least one of caprylic capric triglyceride and caprylic triglyceride.

In some embodiments, the emulsifier is sorbitan oleate (Span 80).

In some embodiments, the content of the active ingredient trefarotene can be 0.001-0.1wt% of the pharmaceutical composition, preferably 0.001-0.01wt%, for example 0.001wt%, 0.002wt%, 0.0025wt%, 0.003wt%, 0.004wt%, 0.005wt%, 0.006wt%, 0.008wt%, etc.

In some embodiments, the content of the oil may be 0.1-20 wt %, preferably 1-10 wt %, such as 1 wt %, 3 wt %, 4 wt %, 5 wt % or 8 wt % of the pharmaceutical composition.

In some embodiments, the content of the emulsifier can be 0.01-10wt% of the pharmaceutical composition, preferably 0.1-7wt%, for example 0.2wt%, 0.8wt%, 1wt%, 1.4wt%, 2wt%, 3.4wt% or 5wt%.

In one embodiment, the pharmaceutical composition comprises the following components: 0.001-0.1 wt% of trefarotene; 2-8 wt% of oil; 0.2-6 wt% of emulsifier, and water added to 100 wt%.

In a further embodiment, the pharmaceutical composition of the present invention may optionally include at least one of a solubilizer, an emulsifying thickener, and a pH adjuster.

Preferably, the solubilizing agent is selected from one or both of phenoxyethanol and ethanol.

In some embodiments, the content of the solubilizer may be in the range of 0.5 to 10 wt % of the pharmaceutical composition, preferably 0.6 to 8 wt %, such as 0.8 wt %, 4 wt % or 6 wt %.

Preferably, the emulsifying thickener is selected from at least one of polyacrylamide emulsifying thickeners (such as SEPIGEL 305, SIMULGEL EG, SIMULGEL FL, SIMULGEL 600 from SEPPIC) and acrylate emulsifying thickeners (such as Pemulen TR-1 or 2 from Lubrizol); more preferably, the emulsifying thickener is Pemulen TR-1.

In some embodiments, the content of the emulsifying thickener can be 0.1-5wt% of the pharmaceutical composition, preferably 0.2-2wt%, for example 0.4wt%, 0.5wt%, 0.8wt%, 1wt%.

Preferably, the pH regulator is selected from one or both of triethanolamine and sodium hydroxide; more preferably, the pH regulator is triethanolamine. The actual amount of the pH regulator is very small, and only an appropriate amount is needed to adjust the pH of the pharmaceutical composition to 4.5-7.5, preferably 5.0-7.0.

In one embodiment, the pharmaceutical composition of the present invention comprises the following components:

0.001-0.1wt% of trefarotene; 2-8wt% of oil; 0.2-6wt% of emulsifier; 1-8wt% of solubilizer; 0.2-1.0wt% of emulsifying thickener; an appropriate amount of pH regulator to adjust the pH of the pharmaceutical composition to 4.5-7.5; and water to 100wt%.

Preferably, the pharmaceutical composition comprises the following components:

0.001-0.1wt% of trefarotene; 2-5wt% of oil; 0.4-3wt% of emulsifier; 1-6wt% of solubilizer; 0.3-0.8wt% of emulsifying thickener; an appropriate amount of pH regulator to adjust the pH of the pharmaceutical composition to 5.0-7.0; and water to 100wt%.

In a further embodiment, the pharmaceutical composition of the present invention may optionally include other pharmaceutically acceptable excipients, such as at least one of a humectant, an antioxidant, a lubricant, a preservative, and the like.

The humectant can be selected from commonly used humectants known in the art, for example, at least one selected from glycerol, propylene glycol, sodium hyaluronate, and allantoin. The humectant can be optionally added in a conventional amount. For example, the content of the humectant can be 0 to 30 wt %, such as 0 to 15 wt %, such as 0.05 wt %, 0.1 wt %, 0.5 wt %, 1 wt %, 5 wt %, 10 wt %, 12 wt % of the pharmaceutical composition.

The antioxidant can be selected from commonly used antioxidants known in the art, for example, selected from at least one of sodium pyrosulfite, sodium bisulfite, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), tocopherol, tocopherol acetate, tocopherol nicotinate, ascorbic acid, ascorbyl tetraisopalmitate, sodium ascorbyl phosphate, and magnesium ascorbyl phosphate. The antioxidant can be optionally added in a conventional amount. For example, the content of the antioxidant can be 0 to 2wt% of the pharmaceutical composition, for example 0 to 1wt%, for example 0.05wt%, 0.1wt%, 0.2wt%, 0.5wt%, and 0.8wt%.

The lubricant can be selected from commonly used lubricants known in the art, for example, at least one selected from cyclomethicone, cyclopolydimethylsiloxane, polymethylsilsesquioxane, and polydimethylsiloxane. The lubricant can be optionally added in a conventional amount. For example, the content of the lubricant can be 0 to 2 wt% of the pharmaceutical composition, such as 0 to 1 wt%, such as 0.05 wt%, 0.1 wt%, 0.3 wt%, 0.5 wt%, 0.8 wt%.

The preservative can be selected from commonly used preservatives known in the art, for example, selected from at least one of phenoxyethanol, benzyl alcohol, butylene glycol, hexylene glycol, pentylene glycol, p-hydroxyacetophenone, ethylhexylglycerin, and methylparaben. The preservative can be optionally added in a conventional amount. For example, the content of the preservative can be 0 to 5wt% of the pharmaceutical composition, such as 0 to 3wt%, such as 0.05wt%, 0.1wt%, 0.2wt%, 0.3wt%, 0.5wt%, 0.8wt%, 1wt%.

In an exemplary embodiment, the pharmaceutical composition of the present invention comprises the following components:

Trifarotene 0.001-0.005wt%; caprylic capric triglyceride and/or caprylic triglyceride 2-8wt%; phenoxyethanol 1-2wt%; ethanol 3-5wt%; sorbitan oleate and/or Labrafil M 1944CS 0.2-3.5wt%; butylated hydroxytoluene 0-0.2wt%; cyclomethicone 0-1.0wt%; Pemulen TR-1 0.3-0.8wt%; propylene glycol 0-15wt%; sodium hyaluronate 0-0.2wt%; an appropriate amount of triethanolamine to adjust the pH of the pharmaceutical composition to 5.0-7.0; water is added to 100wt%.

Trifarotene 0.001-0.005wt%; caprylic capric triglyceride 2-5wt%; phenoxyethanol 1-2wt%; ethanol 3-5wt%; sorbitan oleate 0.2-1wt%; butylated hydroxytoluene 0.1-0.2wt%; cyclomethicone 0.2-1.0wt%; Pemulen TR-1 0.3-0.8wt%; propylene glycol 10-15wt%; sodium hyaluronate 0.05-0.2wt%; appropriate amount of triethanolamine to adjust the pH of the pharmaceutical composition to 5.0-7.0; water is added to 100wt%.

In an exemplary embodiment, the pharmaceutical composition of the present invention includes the following components: 0.005 wt% of trefarotene, 3 wt% of caprylic capric triglyceride, 0.8 wt% of sorbitan oleate, a pH adjuster to adjust the pH of the pharmaceutical composition to 5.0-7.0, and water to 100 wt%.

In an exemplary embodiment, the pharmaceutical composition of the present invention includes the following components: 0.005wt% of trefarotene, 3wt% of caprylic capric triglyceride, 0.8wt% of sorbitan oleate, 1wt% of phenoxyethanol, 3wt% of ethanol, 0.4wt% of Pemulen TR-1, an appropriate amount of pH adjuster to adjust the pH of the pharmaceutical composition to 5.0-7.0, and water is added to 100wt%.

In an exemplary embodiment, the pharmaceutical composition of the present invention includes the following components: 0.0025wt% of trefarotene, 3wt% of caprylic capric triglyceride, 0.8wt% of sorbitan oleate, 1wt% of phenoxyethanol, 3wt% of ethanol, 0.4wt% of Pemulen TR-1, an appropriate amount of pH adjuster to adjust the pH of the pharmaceutical composition to 5.0-7.0, and water is added to 100wt%.

In an exemplary embodiment, the pharmaceutical composition of the present invention includes the following components: 0.001wt% of trefarotene, 3wt% of caprylic capric triglyceride, 0.8wt% of sorbitan oleate, 1wt% of phenoxyethanol, 3wt% of ethanol, 0.4wt% of Pemulen TR-1, an appropriate amount of pH adjuster to adjust the pH of the pharmaceutical composition to 5.0-7.0, and water is added to 100wt%.

In an exemplary embodiment, the pharmaceutical composition of the present invention includes the following components: 0.0025wt% of trefarotene, 4wt% of caprylic capric triglyceride or caprylic triglyceride, 0.8wt% of sorbitan oleate, 1wt% of phenoxyethanol, 3wt% of ethanol, 0.4wt% of Pemulen TR-1, an appropriate amount of pH adjuster to adjust the pH of the pharmaceutical composition to 5.0-7.0, and water is added to 100wt%.

The pharmaceutical composition of the present invention can be prepared according to conventional methods. In one embodiment, the present invention also provides a method for preparing the above pharmaceutical composition, comprising the following steps: mixing trefarotene, oil, emulsifier and water.

In one embodiment, based on the components of the pharmaceutical composition, the method comprises the following steps: 1) mixing trefarotene with oil, emulsifier, and optionally solubilizer; 2) mixing other components (such as emulsifying thickener, humectant, antioxidant, lubricant, preservative, etc., if any) with purified water; 3) mixing and shearing the obtained mixture uniformly, adding a pH adjuster (if any) to adjust the pH to 4.5-7.5 (preferably pH 5.0-7.0), and stirring until uniform.

The D ₅₀ particle size of the pharmaceutical composition of the present invention is ≤5 μm, preferably ≤2 _μm , more preferably ≤1.5 μm, for example ≤1 μm.

The present invention also provides the use of the above-mentioned pharmaceutical composition in the preparation of a drug for preventing and/or treating skin-related diseases. The skin-related diseases include:

1) Acne, including acne vulgaris, acne comedonae, acne polymorpha, rosacea, cystic acne, conglobate acne, senile acne, secondary acne such as solar acne, drug-induced acne or occupational acne;

2) Skin keratosis, including ichthyosis, ichthyosis-like symptoms, lamellar ichthyosis, Darier's disease, palmoplantar keratosis, leukoplakia, pityriasis rubra pilaris and leukoplakia-like symptoms, skin or mucosal (oral) lichen;

3) skin diseases with an inflammatory immunoallergic component, with or without cell proliferation disorders, in particular all forms of psoriasis, whether of the skin, mucous membranes or nails, and even psoriatic arthritis, or atopic dermatitis and various forms of eczema;

4) Skin aging caused by exposure to UV radiation, including photoaging or chronoaging, or for the reduction of actinic keratosis and pigmentation, or any pathological condition associated with chronoaging or photoaging, such as xerosis, pigmentation and wrinkles;

5) symptoms associated with benign skin or epidermal proliferations, whether or not of viral origin, such as cutaneous warts, including common warts, flat warts, molluscum contagiosum, and epidermodysplasia verruciformis, or oral or cauliflower papillomatosis;

6) Skin diseases such as immune skin diseases, such as lupus erythematosus, bullous immune diseases and collagen diseases, such as scleroderma;

7) skin erythema with epidermal and/or dermal atrophy, or skin atrophy induced by topical or systemic corticosteroids;

8) Healing disorders, or for preventing or repairing stretch marks, or for promoting healing;

9) Skin abnormalities caused by fungi, such as athlete's foot and tinea versicolor;

10) Pigmentation disorders such as hyperpigmentation, melasma, hypopigmentation or vitiligo;

11) Symptoms of cancerous or precancerous skin or mucous membranes, such as actinic keratosis, Bowen's disease, carcinoma in situ, keratoacanthoma and skin cancers, such as basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and cutaneous lymphomas, such as T-cell lymphoma.

Preferably, the skin-related disease is selected from acne, skin keratosis, skin aging (including age aging and photoaging), pigmentation, psoriasis, psoriatic arthritis, dermatitis, eczema, skin warts, skin erythema, stretch marks, athlete's foot, and skin cancer.

The pharmaceutical composition of the present invention can be prepared into a variety of preparations, especially topical preparations, such as emulsions, gels, creams, ointments, liniments, etc. The pharmaceutical composition has good stability, small particle size, high uniformity, and low irritation, and effectively improves medication safety and skin comfort.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1. Microscopic particle structures of different pharmaceutical compositions observed under a microscope of the same magnification, wherein A is the pharmaceutical composition 9 of Example 5, B is the commercially available Aklief cream preparation (Galderma); C is the control composition 2 in Control Example 1;

FIG2 is a H&E stained pathological section of the skin irritation test in Test Example 2 of the present invention;

FIG3 is a graph showing the therapeutic effects of different trefarotene preparations on photoaging of nude mouse skin in Test Example 3 of the present invention.

Detailed ways

Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.

The terms "comprises," "comprising," "having," "containing," or "involving" and other variations thereof herein are inclusive or open-ended and do not exclude additional unrecited elements or method steps.

The term "prevention or treatment" means administering the formulation of the present invention to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes: (i) preventing the disease or disease state from occurring in a mammal, especially when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state; (ii) inhibiting the disease or disease state, that is, curbing its development; (iii) alleviating the disease or disease state, even if the disease or disease state regresses.

The term "therapeutically effective amount" means an amount of the formulation of the present invention that (i) treats or prevents a specific disease, condition or disorder, (ii) alleviates, ameliorates or eliminates one or more symptoms of a specific disease, condition or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition or disorder described herein. The amount of the formulation of the present invention that constitutes a "therapeutically effective amount" varies depending on the formulation, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by a person skilled in the art based on his or her own knowledge and the present disclosure. In the present invention, the content of the active ingredient trefarotene in the pharmaceutical composition of trefarotene can be in the range of 0.001 to 0.1 wt%, preferably 0.001 to 0.01 wt%, for example 0.001 wt%, 0.002 wt%, 0.0025 wt%, 0.003 wt%, 0.004 wt%, 0.005 wt%, 0.006 wt%, 0.008 wt%, 0.01 wt%, etc.

The term "pharmaceutically acceptable excipients" refers to substances that have no significant irritation to organisms and will not damage the active ingredients. Suitable excipients may be well known to those skilled in the art.

The term "chemical stability" refers in particular to the stability of the active ingredient.

The term "physical stability" refers in particular to the absence of crystallization or precipitation of the active agent, or the absence of phase separation or color change in the composition.

As non-limiting examples, the composition of the present invention can be prepared into a variety of preparations, especially topical preparations, such as emulsions, gels, creams, ointments, liniments, and the like.

As a non-limiting example, the composition of the present invention can be prepared into a drug for treating skin-related diseases, especially for treating acne, skin keratosis, skin aging (including age aging and photoaging), pigmentation, psoriasis, psoriatic arthritis, dermatitis, eczema, skin warts, skin erythema, stretch marks, athlete's foot, skin cancer, etc.

To select the ingredients of the pharmaceutical composition, the skilled person should also take other parameters into account. In particular, the pharmaceutical composition that can be used as a medicament according to the invention must also be formulated according to the pathological state to be treated.

As a preferred non-limiting example, the pharmaceutical composition of the present invention may have a non-greasy cosmetic appearance, has lubricating and moisturizing properties, and can improve the comfort of skin medication.

The inventors unexpectedly discovered that when sorbitan oleate (Span 80) or oleic acid macrogol glyceride (Labrafil M 1944CS) is used as an emulsifier for a pharmaceutical composition containing trefarotene and oil, a milky white emulsion can be obtained, and the addition of the emulsifier can greatly improve the stability of trefarotene in oil, effectively maintaining the stability of the properties of the pharmaceutical composition. In addition, the inventors conducted experiments using equal or different amounts of other ingredients as emulsifiers, but were unable to obtain a composition with a uniform texture. For example, when poloxamer 188 and poloxamer 407 are used as emulsifiers, the emulsification effect is poor, the appearance is off-white and there are a lot of oil droplets on the surface; when soybean lecithin S100, Tween 20, Tween 80, caprylic capric acid macrogol glyceride (Labrasol) and polyoxyethylene (40) hydrogenated castor oil (RH40) are used as emulsifiers, the oil-water stratification of the system will be caused; when Span 40 is used as an emulsifier, the obtained composition is a viscous paste; when polyglycerol oleate (Plurol Oleique CC) is used as an emulsifier, the composition is relatively viscous, and the physical stability of the emulsion is poor during long-term storage, and the emulsion will break. Therefore, preferably, the emulsifier is sorbitan oleate (Span 80) or oleic acid macrogol glyceride (Labrafil M 1944CS).

The inventors also compared and tested the effects of different oils on the pharmaceutical composition. It was unexpectedly found that the use of oil caprylic capric triglyceride (also known as medium chain triglyceride, medium chain triglyceride) or caprylic triglyceride helps to maintain the stability of the pharmaceutical composition. When other oils, such as monolinoleyl glyceryl, monooleyl glyceryl, etc., are used, the stability of the pharmaceutical composition is poor.

The features and advantages of the present invention are further described below in conjunction with embodiments. It should be understood that the specific embodiments are merely illustrative and do not imply any limitation on the scope of protection of the present invention.

Unless otherwise specified, the materials used in the following examples are all commercially available products, among which caprylic capric triglyceride was purchased from Liaoning Xinxing Pharmaceutical Co., Ltd., caprylic triglyceride was purchased from Jiangsu Southeast Nanomaterials Co., Ltd., Span 80 was purchased from Jiangxi Yipsheng Pharmaceutical Co., Ltd., and Span 83 was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.

Experimental investigation method of drug composition:

pH: Take an appropriate amount of this product and test it according to General Chapter 0631 of Part IV of the 2020 edition of the Chinese Pharmacopoeia.

Particle size: Take about 1g of sample, add 5ml of water, and shake to disperse evenly. Use Mastersizer 3000 particle size analyzer with parameters of The absorption rate is 0.01, the refractive index is 1.458, and the shading degree is about 8%.

Content: The content of trefarotene can be determined by conventional high performance liquid chromatography. Alternatively, the following test conditions can be used:

Column: GL Sciences Inertsil ODS-3V (4.6×150mm, 5μm)

Flow rate: 1.0mL/min

Column temperature: 40°C

Mobile phase A: 0.1% phosphoric acid solution

Mobile phase B: acetonitrile

Gradient elution program:

Sample tray: No temperature control

Injection volume: 20 μL

Detection wavelength: 278nm

Example 1 Preparation of Trifarotene Pharmaceutical Composition

Preparation method: According to the components shown in Table 1, trefarotene, oil, solubilizer and emulsifier are mixed to obtain mixture 1; the emulsifying thickener and water are mixed to obtain mixture 2; mixtures 1 and 2 are mixed, stirred for 30 minutes, a pH adjuster is added to adjust the pH to 5-6, and stirred until uniform to obtain the mixture.

The appearance, pH value, particle size and content of the prepared composition (0 day) and after being placed in a dry environment at 60° C. for 30 days were tested. The specific results are shown in Table 1.

Table 1

Note: “-” indicates not included.

The experimental results show that the above-mentioned pharmaceutical composition has good physical and chemical stability.

Example 2 Preparation of Trifarotene Pharmaceutical Composition

Preparation method: According to the components shown in Table 2, trefarotene, oil, solubilizer, emulsifier, antioxidant and preservative are mixed to obtain mixture 1; emulsifying thickener, moisturizer and water are mixed to obtain mixture 2; mixtures 1 and 2 are mixed, stirred for 30 minutes, sheared for 10 minutes, and pH regulator is added to adjust the pH to 5-6 to obtain the composition. The composition is examined in the same manner as in Example 1.

Table 2

Note: “-” indicates not included.

Example 3 Preparation of Trifarotene Pharmaceutical Composition

Preparation method: According to the components shown in Table 3, trefarotene, oil, solubilizer, emulsifier, lubricant and antioxidant are mixed to obtain mixture 1; emulsifying thickener, moisturizer and water are mixed to obtain mixture 2; mixtures 1 and 2 are mixed, stirred for 30 minutes, sheared for 10 minutes, and pH regulator is added to adjust the pH to 5-6 to obtain the composition. The composition is examined in the same manner as in Example 1.

table 3

Note: “-” indicates not included.

Example 4 Preparation of Trifarotene Pharmaceutical Composition

Preparation method: According to the components shown in Table 4, trefarotene, oil, solubilizer, emulsifier, lubricant and antioxidant are mixed to obtain mixture 1; emulsifying thickener, moisturizer and water are mixed to obtain mixture 2; mixtures 1 and 2 are mixed, stirred for 30 minutes, and a pH regulator is added to adjust the pH to 5-6 to obtain the composition. The composition is examined in the same manner as in Example 1.

Table 4

Note: “-” indicates not included.

Example 5 Preparation of Trifarotene Pharmaceutical Composition

Preparation method: According to the components shown in Table 5, trefarotene, oil, solubilizer, emulsifier, lubricant and antioxidant are mixed to obtain mixture 1; emulsifying thickener, moisturizer and water are mixed to obtain mixture 2; mixtures 1 and 2 are mixed, stirred for 30 minutes, sheared for 10 minutes, and a pH regulator is added to adjust the pH to 5-6 to obtain the composition. The composition is examined in the same manner as in Example 1.

table 5

Note: “-” indicates not included.

Example 6 Preparation of Trifarotene Pharmaceutical Composition

Preparation method: According to the components shown in Table 6, trefarotene, oil, solubilizer and emulsifier are mixed to obtain mixture 1; emulsifying thickener, moisturizer and water are mixed to obtain mixture 2; mixtures 1 and 2 are mixed, stirred for 30 minutes, sheared for 10 minutes, and pH regulator is added to adjust the pH to 5-6 to obtain the composition. The composition is examined in the same manner as in Example 1.

Table 6

Note: “-” indicates not included.

The experimental results show that composition 11 uses Span 80 as an emulsifier and is placed at 60°C for 30 days. The appearance, pH, particle size and content of the composition remain stable, and it has good physical and chemical stability. Composition 12 uses Span 83 as an emulsifier and is placed at 60°C for 30 days. The appearance, pH and particle size of the composition remain stable; but API The content decreased significantly, and the chemical stability was poor. Composition 13 used caprylic triglyceride as the oil and Span 80 as the emulsifier. It was placed at 60°C for 30 days. The appearance, pH, particle size and content remained basically stable, and it had good physical and chemical stability. Composition 14 used mineral oil as the oil and Span 83 as the emulsifier. It was placed at 60°C for 30 days. The appearance, pH and particle size of the composition remained stable; but the API content decreased significantly, and the chemical stability was poor.

Comparative Example 1

Preparation method: According to the components shown in Table 7, trefarotene, oil, solubilizer and emulsifier are mixed to obtain mixture 1; emulsifying thickener and water are mixed to obtain mixture 2; mixtures 1 and 2 are mixed, stirred for 30 minutes, sheared for 30 minutes, and pH regulator is added to adjust the pH to 5-6 to obtain the composition. The composition is examined in the same manner as in Example 1.

Table 7

The control composition 1 does not contain an emulsifier, and the prepared composition is a white emulsion with a particle size D ₅₀ of 12.8 μm. Even after shearing, the particle size is still large, D ₅₀ of 3.39 μm, and the uniformity is poor. The control composition 2 uses polyglycerol oleate (Plurol Oleique CC) as an emulsifier, and the prepared composition is a milky white paste, which is viscous and difficult to apply; and the sample has poor stability. After being placed at 60°C for 30 days, it was observed under a microscope that the emulsion droplets were not round and partially broken (as shown in Figure 1-C).

Comparative Example 2

Preparation method: According to the components shown in Table 8, trefarotene, oil, solubilizer and emulsifier are mixed to obtain a mixture 1; mix the emulsifying thickener and water to obtain mixture 2; mix mixtures 1 and 2, stir for 30 minutes, shear for 10 minutes, add a pH adjuster to adjust the pH to 5-6, and obtain the composition. The composition is examined in the same manner as in Example 1.

Table 8

The experimental results show that a milky white emulsion can be prepared by using monolinoleyl glyceryl and monooleyl glyceryl as oils, but the chemical stability of the resulting pharmaceutical composition is very poor. When placed at 60°C for 30 days, the API content drops below 50%.

Test Example 1. Stability Investigation

The purpose of this test example is to investigate the stability of the topical preparation of trefarotene prepared from the pharmaceutical composition of the present invention. Aklief cream is a trefarotene cream preparation approved by the US FDA for topical treatment of acne, and the commercially available Aklief cream is used as a control.

Sample A: a topical preparation of trefarotene prepared according to the pharmaceutical composition 9 of Example 5; Sample B: a commercially available Aklief cream preparation (Galderma, batch number 334212). The microscopic particle structure of the preparation observed at 40×10 magnification using an Olympus CX41RF microscope is shown in FIG1 . Among them, FIG. A is a topical preparation of trefarotene prepared from the pharmaceutical composition of the present invention, with a small particle size and good uniformity. FIG. B is a commercially available Aklief cream preparation, with a large particle size and poor uniformity.

The physical and chemical properties of samples A and B were investigated under accelerated test (40°C, 75% RH, 3 months) and long-term test (25°C, 60% RH, 3 months) conditions. The experimental results are shown in Table 9 below.

Table 9

The results showed that under the conditions of accelerated test and long-term test, the particle size of the commercially available Aklief cream preparation has a tendency to increase further, indicating that the physical stability is poor. However, the particle size of the topical preparation of trefarotene prepared by the pharmaceutical composition of the present invention remains basically unchanged over time, and the API content also remains stable, indicating that it has good physical and chemical stability. Test Example 2: Skin irritation test

The purpose of this test example is to investigate the irritation of the trefarotene topical preparation prepared from the pharmaceutical composition of the present invention to the skin by comparing the preparation of the present invention with the commercially available Aklief cream.

1. Experimental plan

New Zealand rabbits (2.0-2.5 kg, 16 rabbits, half male and half female, provided by Nanjing Pukou District Life Breeding Farm, production license number: SCXK (Su) 2019-0005) were randomly divided into 4 groups, 4 rabbits in each group, half male and half female. Different test drugs were administered once a day for 7 consecutive days. The different groups were:

Group I: positive control group, commercially available Aklief cream preparation (Galderma, batch number 334212);

Group II: trefarotene topical preparation prepared according to pharmaceutical composition 7 of Example 4;

Group III: trefarotene topical preparation prepared according to pharmaceutical composition 9 of Example 5;

Group IV: trefarotene topical preparation prepared according to pharmaceutical composition 5 of Example 3.

2. Experimental methods:

A baby pusher was used to remove hair from the back of the rabbit (no razor or depilatory cream was used, and the skin should not be damaged); the area of each shaved area was approximately 5×5 ^cm2 . The depilatory area must have clear and neat boundaries and the depilatory area must be consistent. 24 hours after depilation, 1 mL of the corresponding preparation was applied to the depilatory area, and the drug was administered once a day for 7 consecutive days. Before each administration, the test drug was washed off with distilled water, and the test drug was applied after the skin of the rabbit's administration area was dried. 24 hours after each administration (expressed as days-24 hours in Table 12) and 1 hour after the last administration (7-1h in Table 12), the skin reaction was observed with the naked eye under natural light. Score according to Table 10, and judge the irritation intensity according to Table 11. The scoring method refers to the "Technical Guidelines for Studies on Irritancy, Allergy and Hemolysis of Chemical Drugs". The results of the skin irritation intensity scoring are shown in Table 12. At the end of the observation period, a histopathological examination was performed, and H&E stained pathological sections were The film is shown in Figure 2.

Table 10 Skin irritation rating

Note: Skin irritation reaction includes erythema and edema, with a maximum total score of 8 points.

Table 11 Evaluation criteria for skin irritation intensity

3. Experimental results

Table 12 Results of rabbit skin irritation intensity scoring

Note: In the above table, "1-24h" refers to the 24th hour observation after administration on the first day; "7-1h" refers to the 1st hour observation after administration on the 7th day; and so on.

From the irritation scoring results in the above table, it can be seen that on the first day, all groups scored 0, which is non-irritating. On the second day, the scores of groups I to III were 0.5, and the rabbit skin began to show mild irritation; the score of group IV was 0, and the rabbit skin was non-irritating. On the third day, the scores of groups I and III were 0.75, and the rabbit skin showed mild irritation; the scores of groups II and IV were 0, and there was no irritation. On the fourth day, the score of group I was 1.75, the score of group II was 0.75, and the rabbit skin showed mild irritation; there was no irritation in groups III and IV; on the fifth day, the score of group I was 2, the scores of groups II and III were 1, and the score of group IV was 0.75, and all groups showed mild irritation. On the 6th to 7th day, group I (positive control group) scored 3 to 4, showing moderate irritation; the scores of groups II to IV (the trefarotene preparation of the present invention) were <2.99, and still only showed mild irritation. In summary, the skin irritation of the Aklief cream preparation group is the most obvious, and the trefarotene preparation of group III of the present invention is the least irritating.

In addition, the H&E staining pathological pictures in Figure 2 show that in group I, obvious hemorrhage and edema can be seen in the dermis, a large number of inflammatory cells infiltrated, a large number of eosinophils (one of the signs of skin allergic reactions) can be seen, the capillaries of the subcutaneous tissue are obviously dilated, and a large number of inflammatory cells infiltrate around the blood vessels; in group II, the inflammatory cell infiltration in the dermis was significantly reduced compared with group I, no obvious eosinophils were seen, there was a small amount of bleeding in the dermis, dilation of blood vessels in the subcutaneous tissue, and inflammatory cell infiltration around the blood vessels; in group III, the inflammatory cell infiltration in the dermis was significantly reduced compared with group I, there were only a few bleeding spots in the dermis, slight dilation of blood vessels in the subcutaneous tissue, and a small amount of inflammatory cell infiltration around the blood vessels; in group IV, the inflammatory cell infiltration in the dermis was significantly reduced compared with group I, no obvious eosinophils were seen, a small amount of bleeding can be seen in the dermis, dilation of blood vessels in the subcutaneous tissue, and inflammatory cell infiltration around the blood vessels. In summary, the inflammatory reaction and allergic reaction of groups II, III, and IV were better than those of group I, but group III had the best effect (the mildest bleeding and inflammation) and the least irritation.

The experimental results show that the Aklief cream preparation has obvious skin irritation during use, while the pharmaceutical composition of the present invention significantly reduces the irritation of the preparation to the skin and improves the compliance and comfort of the subjects during use.

Test Example 3: Drug Efficacy Test

The purpose of this test example is to compare the preparation of the present invention with the commercially available tretinoin cream. By comparison, the effect of the topical preparation of trefarotene prepared by the pharmaceutical composition of the present invention on the treatment of photoaging of the skin was investigated. Retinoic acid cream is a product approved by the US FDA for the treatment of photoaging.

1. Dosage regimen

56 healthy nude mice (weight 20-25g, Changzhou Cavens Experimental Animal Co., Ltd.) were randomly divided into 4 groups, half male and half female, and administered according to the dosing regimen in Table 13, where:

Blank control group: placebo, the difference from the test drug group is that the placebo does not contain trefarotene;

Positive control group: Retinoic acid cream (concentration 0.02%, Ortho Pharmaceuticals, batch number 356979);

The low-dose group of the present invention: the concentration of trefarotene is 0.001%, and the prescription is the same as that of the pharmaceutical composition 9 of Example 5, except that the content of trefarotene is different;

The high-dose group of the present invention: trefarotene concentration 0.005%, i.e., pharmaceutical composition 9 of Example 5;

Table 13 Dosage regimen

2. Test methods

Take one UVA lamp and one UVB lamp, the lamp height is 13cm, the UVA irradiation intensity is 0.7546mW/ ^cm2 , the UVB irradiation intensity is 0.0269mW/ ^cm2 , once a day, 5 days a week. Minimum erythema dose (MED), UVA irradiation dose is 1850mJ/ ^cm2 , UVB irradiation dose is 220mJ/ ^cm2 ; in the first week, irradiation is carried out according to 70% of the minimum erythema dose (MED), UVA increases by 650mJ/ ^cm2 every week, UVB increases by 30mJ/ ^cm2 every week; after 6 weeks of irradiation, the cumulative dose of UVA is 71.5J/ ^cm2 , and the cumulative dose of UVB is 6mJ/ ^cm2 .

The nude mice were medicated according to the above experimental scheme. The irradiated area on the back of the nude mice was photographed once a week to observe the treatment effect (as shown in Figure 3), and then the skin on the back of the nude mice was scored according to the scoring criteria, and the evaluation criteria are shown in Table 14. The scoring results are shown in Table 15.

Table 14 Photoaging nude mouse skin scoring table

Table 15 Results of skin wrinkle scoring in nude mice after 2 weeks of drug administration

As shown in Table 15, the score of the blank control group was 4.36, that of the low-dose trefarotene group of the present invention was 1.36, and that of the high-dose trefarotene group was 1.14, indicating that the test drug trefarotene has a good therapeutic effect on skin photoaging.

In addition, surprisingly, although the concentration of trefarotene in the test drugs of the present invention at different doses is much lower than that of the positive control drug retinoic acid (0.02%), the skin wrinkle scores of the trefarotene at different doses are better than those of the positive control group and much better than those of the blank group, showing a superior anti-wrinkle efficacy.

In summary, the pharmaceutical composition of the present invention can be prepared into a trefarotene topical preparation with uniform texture and small particle size, and various components including oils and emulsifiers have good compatibility with the active ingredient trefarotene, so that the composition can maintain good physical and chemical stability, and has very low irritation, good medication safety and skin comfort.

Through the above embodiments and test examples, those skilled in the art can better understand the characteristics and advantages of the present invention. However, the technical solution of the present invention is not limited to the above embodiments, and any modification, equivalent replacement, improvement, etc. made to the components and dosage ratio of the pharmaceutical composition within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

A pharmaceutical composition containing trefarotene, comprising trefarotene, oil, emulsifier and water;

The oil is selected from at least one of caprylic capric triglyceride, caprylic triglyceride, isopropyl myristate, and mineral oil;

The emulsifier is selected from at least one of sorbitan oleate and oleic acid macrogol glyceride.
The pharmaceutical composition according to claim 1, wherein:

The content of trefarotene is 0.001-0.1wt% of the pharmaceutical composition, preferably 0.001-0.01wt%;

The content of the oil is 0.1 to 20 wt % of the pharmaceutical composition, preferably 1 to 10 wt %;

The content of the emulsifier is 0.01 to 10 wt % of the pharmaceutical composition, preferably 0.1 to 7 wt %.
The pharmaceutical composition according to claim 1 or 2, wherein: the pharmaceutical composition comprises the following components: 0.001-0.01wt% of trefarotene; 2-8wt% of oil; 0.2-6wt% of emulsifier, and water is added to 100wt%.
The pharmaceutical composition according to any one of claims 1 to 3, wherein: the pharmaceutical composition comprises at least one of a solubilizer, an emulsifying thickener, and a pH adjuster;

Preferably, the solubilizer is selected from at least one of phenoxyethanol and ethanol; the content of the solubilizer is 0.5-10wt% of the pharmaceutical composition;

Preferably, the emulsifying thickener is selected from at least one of polyacrylamide emulsifying thickeners and acrylate emulsifying thickeners; the content of the emulsifying thickener is 0.1 to 5 wt% of the pharmaceutical composition;

Preferably, the pH adjuster is selected from at least one of triethanolamine and sodium hydroxide; the content of the pH adjuster is an appropriate amount to adjust the pH of the pharmaceutical composition to 4.5-7.5.
The pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutical composition comprises the following components:

0.001-0.1wt% of trefarotene; 2-8wt% of oil; 0.2-6wt% of emulsifier; 1-8wt% of solubilizer; 0.2-1.0wt% of emulsifying thickener; an appropriate amount of pH regulator to adjust the pH of the pharmaceutical composition to 4.5-7.5; and water to 100wt%.

Preferably, the pharmaceutical composition comprises the following components:

0.001-0.1wt% of trefarotene; 2-5wt% of oil; 0.4-3wt% of emulsifier; 1-6wt% of solubilizer; 0.3-0.8wt% of emulsifying thickener; an appropriate amount of pH regulator to adjust the pH of the pharmaceutical composition to 5.0-7.0; and water to 100wt%.
The pharmaceutical composition according to any one of claims 1 to 5, wherein: the pharmaceutical composition comprises a moisturizing

At least one of an agent, an antioxidant, a lubricant, and a preservative;

Preferably, the moisturizing agent is selected from at least one of glycerin, propylene glycol, sodium hyaluronate and allantoin; the content of the moisturizing agent is 0 to 30 wt % of the pharmaceutical composition;

Preferably, the antioxidant is selected from at least one of sodium pyrosulfite, sodium bisulfite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherol, tocopherol acetate, tocopherol nicotinate, ascorbic acid, ascorbyl tetraisopalmitate, sodium ascorbyl phosphate, and magnesium ascorbyl phosphate; the content of the antioxidant is 0 to 2 wt% of the pharmaceutical composition;

Preferably, the lubricant is selected from at least one of cyclomethicone, cyclopolydimethylsiloxane, polymethylsilsesquioxane, and polydimethylsiloxane; the content of the lubricant is 0 to 2 wt% of the pharmaceutical composition;

Preferably, the preservative is selected from at least one of phenoxyethanol, benzyl alcohol, butylene glycol, hexylene glycol, pentylene glycol, p-hydroxyacetophenone, ethylhexylglycerin, and methylparaben; and the content of the preservative is 0 to 5 wt % of the pharmaceutical composition.
The pharmaceutical composition according to any one of claims 1 to 6, wherein: the pharmaceutical composition comprises the following components: 0.001-0.005wt% of trefarotene; 2-8wt% of caprylic capric triglyceride and/or caprylic triglyceride; 1-2wt% of phenoxyethanol; 3-5wt% of ethanol; 0.2-3.5wt% of sorbitan oleate and/or Labrafil M 1944CS; 0-0.2wt% of butylated hydroxytoluene; 0-1.0wt% of cyclomethicone; 0.3-0.8wt% of Pemulen TR-1; 0-15wt% of propylene glycol; 0-0.2wt% of sodium hyaluronate; an appropriate amount of triethanolamine to adjust the pH of the pharmaceutical composition to 5.0-7.0; and water is added to 100wt%;

Preferably, the pharmaceutical composition comprises the following components: 0.001-0.005wt% of trefarotene; 2-5wt% of caprylic capric triglyceride; 1-2wt% of phenoxyethanol; 3-5wt% of ethanol; 0.2-1wt% of sorbitan oleate; 0.1-0.2wt% of butylated hydroxytoluene; 0.2-1.0wt% of cyclomethicone; 0.3-0.8wt% of Pemulen TR-1; 10-15wt% of propylene glycol; 0.05-0.2wt% of sodium hyaluronate; an appropriate amount of triethanolamine, adjust the pH to 5.0-7.0, and add water to 100wt%.
The pharmaceutical composition according to any one of claims 1 to 7, wherein: the D50 particle size of the pharmaceutical composition is ≤5 μm, preferably, ≤2 μm.
The pharmaceutical composition according to any one of claims 1 to 7, wherein the pharmaceutical composition is a topical preparation, and the topical preparation is selected from at least one of an emulsion, a gel, a cream, an ointment, and a liniment.
Use of the pharmaceutical composition according to any one of claims 1 to 9 in the preparation of a drug for treating skin-related diseases;

Preferably, the skin-related disease is selected from acne, skin keratosis, skin aging including chronological aging and photoaging, pigmentation, psoriasis, psoriatic arthritis, dermatitis, eczema, skin warts, skin erythema, stretch marks, athlete's foot, and skin cancer.