CN111557900A

CN111557900A - Cannabidiol cream, preparation method and application thereof

Info

Publication number: CN111557900A
Application number: CN202010440709.9A
Authority: CN
Inventors: 梁文飞; 粟艳婷; 程幸运
Original assignee: Guangzhou Dazhou Biomedical Technology Co ltd
Current assignee: Guangzhou Dazhou Biomedical Technology Co ltd
Priority date: 2020-05-22
Filing date: 2020-05-22
Publication date: 2020-08-21
Anticipated expiration: 2040-05-22
Also published as: CN111557900B

Abstract

The invention relates to the field of medicinal preparations, in particular to cannabidiol cream, a preparation method and application thereof. The cannabidiol cream can enable cannabidiol to enter local parts of the skin and accumulate in different layers of the skin, and the concentration of the cannabidiol in the skin is improved, so that the cannabidiol can inhibit local inflammatory reaction, and inflammatory skin diseases are treated. In addition, the moisturizer and the emollient in the cream can provide moisturizing and moisture-keeping effects, so that the barrier function of the skin is repaired, and the treatment of inflammatory skin diseases is accelerated.

Description

Cannabidiol cream, preparation method and application thereof

Technical Field

The invention relates to the field of medicinal preparations, in particular to cannabidiol cream, a preparation method and application thereof.

Background

Skin is the first line of physiological defense and the largest organ of the human body, and therefore, when the physiological functions of the skin are damaged, skin diseases can be caused. The most common skin diseases are inflammatory skin diseases such as various dermatitis including atopic dermatitis, contact dermatitis, neurodermatitis, seborrheic dermatitis, allergic dermatitis, and acne, psoriasis, etc. which are chronic inflammatory skin diseases.

Among them, Atopic Dermatitis (AD) is a chronic, recurrent, inflammatory skin disease, and patients often have severe pain and itching, which seriously affects the quality of life. The disease usually begins in infancy, and the disease accounts for about 50% of all patients before age 1, and the disease is passed through chronically, and the disease of some patients can be delayed to adults, but there are also adult patients. The exact pathogenesis of atopic dermatitis is not clear, and it is generally considered that based on genetic factors, as allergens colonize human and microorganisms, cutaneous immune abnormal reactions and inflammation are formed, causing rash and pain and itching, and skin inflammation may be further aggravated by adverse stimuli such as scratching and excessive washing. The treatment of atopic dermatitis mainly includes basic treatment, topical drug treatment and systemic treatment. Topical drug therapy mainly involves topical glucocorticoids, topical calcineurin inhibitors. However, most AD patients currently have recurrent episodes that cannot be eradicated. And the existing therapeutic drugs are also limited in use due to problems of effectiveness, durability and safety.

Contact dermatitis (Contact dermatitis) refers to the inflammatory response of the skin or mucous membrane after single or multiple exposure to exogenous substances, manifested as erythema, swelling, papules, blisters and even bulla. Severe contact dermatitis can cause bullous blisters, erosion, fluid seepage and incrustation due to blister rupture, and even deep dermal ulcer. The treatment of contact dermatitis includes finding contact source, oral histamine medicine, and topical medicine treatment. Creams and lotions are used more frequently in acute and subacute treatments.

Neurodermatitis (Neurodematis), also known as lichen simplex chronicus, is a chronic skin disease characterized by paroxysmal cutaneous pruritus and lichen. Neurodermatitis is also a kind of dermatitis, and mental factors are mainly considered to be a main cause of the disease at present. The main treatment mode is that the histamine medicine, calcium agent and the like are adopted for systemic treatment, and glucocorticoid ointment, cream and the like are adopted for local treatment.

Seborrheic dermatitis (seborrhoeic dermatitis) is a kind of dermatitis, which is better at the parts with vigorous sebum secretion, and is often seen in young people. Excessive secretion of sebum is considered to be an important cause of seborrheic dermatitis.

Allergic dermatitis (Allergic dermatitis) is an inflammatory reaction of the skin caused by many factors and belongs to the category of Allergic diseases. The onset of the disease is greatly related to diet, environment and life style, and generally is caused by allergy to a certain substance, and the symptoms disappear gradually after leaving the allergen. In case of disease, the symptoms of dermatitis should be controlled as soon as possible, and allergens should be searched for, far from the sensitizing factors.

Acne (ace) is a chronic inflammatory skin disease of the pilosebaceous unit, which is easily developed in adolescents, and is characterized by polymorphic skin lesions such as acne, papules, pustules, nodules and the like which are easily developed in the face in clinical manifestation. Current treatment means include daily care, topical medications, chemotherapy, physical therapy, and the like.

Psoriasis is commonly called psoriasis, is a chronic inflammatory skin disease, is easy to relapse, has a long course of disease, is mainly clinically expressed by erythema and scale, is related to hyperproliferation of skin cells of the psoriasis, and has an unknown pathogenesis. At present, no specific treatment is available.

Cannabidiol is one of the cannabinoids isolated from the plant cannabis sativa and is a non-addictive component of the cannabinoids. Clinical tests show that cannabidiol has the effects of treating epilepsy, resisting anxiety, tranquilizing mind, treating movement disorder, relieving pain and the like. Meanwhile, multiple studies show that cannabidiol generates anti-inflammatory activity by regulating the production of cytokines, and can be locally applied to treat inflammatory skin diseases. Palmieri et al found that the skin symptoms were significantly improved in 20 patients with psoriasis or atopic dermatitis, respectively, using cannabidiol ointment in high purity for three months, and that the symptoms could be concluded to be improved as scored by the psoriasis score (PASI) criteria.

There are several possibilities for studying the mechanism by which CBD inhibits inflammation. The first possibility is to activate the arene receptor (AhR) and thus modulate the immune response. Epithelial Lymphocytes (IELs) are present in the skin and are the first line of defense in the skin and may also promote the reorganization and loss repair of skin disorders. While the arene receptor (AhR) manages the number of epithelial lymphocytes (IELs) in the skin and mucosa. Hoffman's research indicates that CBD regulates the number of IELs by binding AhR, ultimately modulating the immune response, acting as an anti-inflammatory. The Meglio study shows that the arene receptor AhR is one of the pathological causes of psoriasis and that ligands capable of activating AhR (such as CBD) can alleviate the inflammatory symptoms in patients with psoriasis. According to the research, the CBD concentration required for activating AhR is 10³～10⁸pM。

The second possibility is that CBD acts through the cannabinoid receptor pathway. Studies by Stefania et al found that cannabidiol can elevate the levels of endogenous cannabinoid (AEA) and inhibit the release of monocyte chemoattractant protein-2 (MCP-2), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor-alpha in an in vitro model of allergic contact dermatitis, thereby inhibiting skin inflammation. Studies by Jonathan d.wilkinson et al found that cannabinoids, including cannabidiol, may inhibit the proliferation of human keratinocytes through the mechanism of cannabinoid receptor 1/2(CB1/CB2), cannabidiol has potential for the treatment of psoriasis due to its involvement in hyperproliferation of human skin.

Third, the research of Attila Ol h et al finds that cannabidiol can inhibit the generation of fat and the proliferation of sebaceous gland cells, and simultaneously has the effects of inhibiting inflammation and resisting malignant cell proliferation by inhibiting NF-kB and other pathways, thereby having potential application in the treatment of acne.

In addition, the research of Mariangela Pucci et al found that cannabidiol can control the proliferation and differentiation of cells by significantly increasing the methylation level of keratin 10 gene DNA and systemic DNA, indicating that cannabidiol has potential for the treatment of skin diseases such as psoriasis.

Topical preparations are the major dermatologic drugs, which have the advantage of maintaining a high drug concentration at the site of application, resulting in a local effect. Meanwhile, for partial diseases such as atopic dermatitis and eczema, moisture retention of the skin and skin moisturizing are important means for treatment, because the emollient can restore the barrier function of the skin, prevent the evaporation of moisture and restore damaged skin. In Zhong atopic dermatitis guideline for diagnosis and treatment (2014 edition), external use of emollients is the fundamental treatment of atopic dermatitis, which is a means before topical drug therapy and systemic therapy, and it is recommended to use the emollients at least twice a day, and the moisturizers and emollients should be used immediately after bathing. At present, cannabidiol is prepared into various dosage forms, but no dosage form which can achieve local high concentration in the skin stroke and has the function of moisturizing exists at present.

For example, the prior art provides a cannabidiol composition which is formulated to a high concentration topically by volatile solvent silicones, but which does not contain any oil phase base, moisturizers and emollients and does not provide a comfortable spreadability and moisturization. In addition, researchers disclose cannabidiol ointment with swelling and pain relieving effects and a preparation method thereof, and the ointment is prepared from the following components, by weight, 5-7 parts of cannabidiol, 3-5 parts of musk, 3-5 parts of ivy, 3-5 parts of tinospora sinensis, 1-2 parts of pearl, 1-2 parts of herba siegesbeckiae, 1-2 parts of safflower, 1-2 parts of rhizoma drynariae, 1-2 parts of lycopodium clavatum, 1-2 parts of lithospermum, 1-2 parts of humulus scandens, 1-2 parts of tribulus terrestris, 1-2 parts of castor bean, 1-2 parts of fructus evodiae, 1-2 parts of mistletoe, 1-2 parts of smilax china leaves, 1-2 parts of polygonum hydropiper, 40-60 parts of glycerol and 906-943 parts of yellow vaseline; the preparation method comprises the following specific steps: step 1, weighing; step 2, crushing and mixing; step 3, preparing and mixing; and 4, filling. The adjuvants of the preparation are traditional Chinese medicines, have undefined functions, and cannot form high concentration of cannabidiol on local skin or provide moisture retention.

Disclosure of Invention

In view of the above, the present invention provides cannabidiol cream, a preparation method and uses thereof. The cream provides a high local concentration of cannabidiol accumulated in the skin, does not substantially enter the blood circulation, and is suitable for topical application to skin conditions.

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

the invention provides cannabidiol cream which is water-in-oil cream and comprises the following components in parts by weight:

the oil phase matrix comprises: one or more of glyceryl monostearate, stearic acid, white vaseline, paraffin, liquid paraffin, light liquid paraffin, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, medium chain fatty glyceride, mineral oil, hydrogenated castor oil, linoleic acid, beeswax, oleic acid, oleyl alcohol, and lanolin;

the emulsifier comprises:

oleique CC497, polysorbate 80, polysorbate 60, polysorbate 20, sorbitan fatty acid ester 80, sorbitan fatty acid ester 40, sorbitan fatty acid ester 20, Labrasol, Transcutol P, stearic acid, glyceryl monostearate, polyoxyethylene 10 oleyl ether, polyoxyethylene 20 oleyl ether, PEG-40 stearate;

the emollient comprises one or more of isopropyl myristate, isopropyl palmitate, cyclomethicone and dimethicone;

the humectant comprises one or more of glycerol, propylene glycol, amino acid, urea, xylitol and sorbitol.

In some embodiments of the invention, the cannabidiol cream further comprises a combination of one or more of a penetration enhancer, a preservative, a stabilizer;

the adhesive comprises the following components in parts by weight:

in some embodiments of the invention, the penetration enhancer comprises Transcutol P, Labrasol,

m1944CS, oleic acid, oleyl alcohol, levulinic acid, menthol or combinations thereof;

the preservative comprises one or more of sorbic acid, benzyl alcohol, phenethyl alcohol, ethylparaben, platinomethyl and propylparaben;

the stabilizer comprises one or more of citric acid, ascorbic acid, Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), tocopherol, and sodium chloride.

In some embodiments of the invention, the emulsifier has an HLB value of 4 to 8.

In some embodiments of the present invention, the composition comprises the following components in percentage by weight:

in some embodiments of the present invention, the composition comprises the following components in parts by weight:

or

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Cream (cream) refers to a uniform semisolid external preparation formed by dissolving or dispersing a drug in a milky liquid type matrix, and an oil phase and an aqueous phase are required to form an emulsifying system, including a water-in-oil type and an oil-in-water type. The cream is uniformly and finely spread, can dissolve and disperse uniform fat-soluble medicines, has the effects of moisturizing and moistening the skin, and is common in atopic dermatitis and dermatitis diseases. Because the cannabidiol is a fat-soluble drug, the lipid-water partition coefficient (LogP) is 6.5, and the cannabidiol has very strong hydrophobicity, when the cannabidiol is prepared into the water-in-oil type cream, the cannabidiol is dissolved in the oil phase, so that the in-vitro release rate and stability of the cannabidiol can be improved, and the cumulative concentration of the cannabidiol in the skin can be improved. Moisturizers may also be added to the creams to provide a moisturizing effect.

On the basis of the research, the invention also provides a preparation method of the cannabidiol cream, which comprises the following steps:

step 1: preparing an oil phase, mixing an oil phase matrix, an emulsifier, an emollient (isopropyl myristate, isopropyl palmitate), a penetration enhancer (transcutol P) and a preservative, heating to 60-80 ℃ for melting, and dissolving cannabidiol in the oil phase;

step 2: preparing a water phase, mixing auxiliary materials in the water phase, including a water phase solvent (water or propylene glycol), a humectant and a stabilizer, and heating to 60-80 ℃;

and step 3: adding the water phase into the oil phase under the stirring state of 900-1200 rpm, maintaining the temperature at 60-80 ℃, and shearing and emulsifying;

and 4, step 4: and (3) placing the mixture at the temperature of 25 +/-5 ℃, cooling the mixture, and continuously stirring the mixture for 0.5 to 1 hour at the speed of 800 to 1000rpm to obtain the emulsifiable paste.

In some embodiments of the present invention, the rotation speed of the emulsification is 900 to 1200rpm, and the emulsification time is 20 to 60 min.

In some embodiments of the invention, the stirring speed of the cooling is 800 to 1000rpm, and the stirring time of the cooling is 0.5 to 1 hour.

The invention also provides the application of the cannabidiol cream or the cannabidiol cream prepared by the preparation method in preparing a medicament for treating and/or preventing skin diseases.

In some embodiments of the invention, the skin disorder comprises one or more of atopic dermatitis, contact dermatitis, neurodermatitis, seborrheic dermatitis, allergic dermatitis, acne, psoriasis.

The present invention provides a water-in-oil cannabidiol cream which is useful for topical application to inflammatory skin conditions. The in vitro release rate demonstrated that cannabidiol in water-in-oil form could be rapidly released from the paste. In vitro permeability experiments and skin residue experiments prove that the cannabidiol in the cannabidiol cream can be released, can enter a stratum corneum, an upper epidermis layer and a dermis layer in the skin, and can be deposited in the stratum corneum, the upper epidermis layer and the dermis layer to exert the drug effect, but only a very small amount of cannabidiol can permeate the skin to enter blood circulation, so that when the cannabidiol cream is used as a local drug for treating skin diseases, systemic adverse reactions can be avoided. Stability data prove that the stabilizing agent such as citric acid added into the composition can provide a medium-weak acidic storage condition for the cannabidiol, effectively inhibit the degradation of the cannabidiol and ensure the stability of the cream.

Since CBD has anti-inflammatory properties, the cream of the invention can accumulate on the local skin and has moisturizing properties, suitable for the treatment of dermatological diseases mainly characterized by inflammatory symptoms, such as atopic dermatitis, contact dermatitis, neurodermatitis, seborrheic dermatitis, allergic dermatitis, acne, psoriasis.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below.

FIG. 1 shows a comparison of in vitro release of cannabidiol cream from different emulsification systems;

FIG. 2 shows in vitro permeability results on a diffusion cell model;

FIG. 3 shows the residual amount of CBD in each layer of skin at different time points after administration of cannabidiol cream on whole pigskin;

FIG. 4 shows a comparison of the drug residue levels of CBD cream on pig skin at different sites;

figure 5 shows the effect of CBD cream concentration on the amount of CBD entering the skin.

Detailed Description

The invention discloses cannabidiol cream, a preparation method and application thereof, and a person skilled in the art can realize the cannabidiol cream by properly improving process parameters by referring to the content. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of this invention without departing from the spirit and scope of the invention.

The invention provides the following technical scheme:

(1) the proposal is a water-in-oil type cream which consists of cannabidiol, one or more oil phase matrixes, one or more emulsifiers, a water phase, an emollient and a humectant.

(2) The cream may further comprise one or more penetration enhancers, one or more co-emulsifiers, a preservative, a stabilizer, and a small amount of sodium chloride.

(3) Wherein the concentration of cannabidiol in (1) is at least 1% and at most 10%.

(4) Wherein the oil phase matrix(s) in (1) comprises glyceryl monostearate, stearic acid, white vaseline, paraffin, liquid paraffin, light liquid paraffin, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, medium chain fatty glyceride, mineral oil, hydrogenated castor oil, linoleic acid, beeswax, oleic acid, oleyl alcohol, and lanolin.

(5) Wherein the emulsifier in (1) can be

Oleique CC497, polysorbate 80, polysorbate 60, polysorbate 20, sorbitan fatty acid ester 80, sorbitan fatty acid ester 40, sorbitan fatty acid ester 20, Labrasol, Transcutol P, stearic acid, glyceryl monostearate, polyoxyethylene 10 oil ether, polyoxyethylene 20 oil ether, PEG-40 stearate, or two therebetweenOr a combination of a plurality of them.

(6) Wherein the proportion of the water phase in the step (1) is 0-40%.

(7) Wherein the humectant in (2) can be glycerol, propylene glycol, amino acid, urea, xylitol, or sorbitol.

(8) Wherein the emollient in (2) can be isopropyl myristate, isopropyl palmitate, cyclomethicone, and dimethicone.

(9) Wherein one or more penetration enhancers in (2) include Transcutol P, Labrasol,

m1944CS, oleic acid, oleyl alcohol, levulinic acid, menthol.

(10) Wherein, the coemulsifier in (2) can be one or the combination of stearic acid and glycerin monostearate.

(11) Wherein, the preservative in the step (2) can be sorbic acid, benzyl alcohol, phenethyl alcohol, ethylparaben, platinomethyl and propylparaben, and the dosage is 0.02-1 percent.

(14) Wherein the stabilizer in (2) may be citric acid, ascorbic acid, Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), or tocopherol.

(15) The cream in (1) is a water-in-oil type emulsifier, the HLB value required by the oil phase in the cream is 4-8, and the HLB value provided by the emulsifier or the emulsifier combination is 4-8.

(16) The cannabidiol cream can be used for treating inflammatory skin diseases, including various dermatitis, such as atopic dermatitis, allergic dermatitis, contact dermatitis, neurodermatitis, seborrheic dermatitis, and acne and psoriasis which are chronic inflammatory reactions.

The formulation is as follows:

the preparation method comprises the following steps: (1) preparing an oil phase: the adjuvants as oil phase were weighed and added to a suitable beaker. The adjuvants as the oil phase include oil phase matrix (white vaseline, paraffin, beeswax, light liquid paraffin, medium-chain fatty glyceride, stearin, stearic acid, cetyl alcohol, stearyl alcohol, lanolin, hydrogenated castor oil, mineral oil, oleyl alcohol, oleic acid, etc.), emollient (isopropyl myristate, isopropyl palmitate, cyclomethicone, dimethyl silicone, etc.), emulsifier (polysorbate 80, sorbitan fatty acid ester 40, sorbitan fatty acid ester 20, Plurol Oleique CC497, Transcutol P, Labrasol, polyoxyethylene 10 oleyl ether, polyoxyethylene 20 oleyl ether, PEG-40 stearate, etc.), and antiseptic (benzyl alcohol, methyl paraben, ethylparaben, propyl paraben, phenethyl alcohol, etc.). After mixing, heating the oil phase to 60-80 ℃ to completely dissolve, and stirring uniformly at 900-1200 rpm.

(2) Adding cannabidiol: weighing needed cannabidiol, adding the cannabidiol into the oil phase which is melted and uniformly mixed in the step (1), and stirring to completely dissolve and uniformly mix.

(3) Preparing a water phase: the adjuvants are weighed as an aqueous phase and added to a suitable beaker. The adjuvants for the water phase include water phase solvent, stabilizer (water soluble adjuvants such as citric acid and ascorbic acid), and humectant. After mixing, heating the water phase to the same temperature (60-80 ℃) as the oil phase to completely dissolve the water phase, and uniformly mixing.

(4) Emulsification: and slowly adding the water phase (not more than 20ml/min) into the oil phase under the conditions of heating to 60-80 ℃ and stirring until the water phase is completely added, rotating at 900-1200 rpm, and stirring for 20-60 minutes at 60-80 ℃. And taking the emulsion off from the heating state, placing the emulsion in a temperature of 25 +/-5 ℃, continuously stirring, naturally cooling the emulsion in the stirring state, wherein the stirring speed of cooling is 800-1000 rpm, and stopping stirring after 0.5-1 h to obtain the cream.

Key technical parameters are as follows:

mixing oil phase and water phase: adding into oil phase from water phase

Emulsification temperature: 60-80 ℃;

the emulsifying and stirring speed is as follows: 900 to 1200 rpm;

and (3) emulsifying time: 20-60 min;

cooling and stirring speed: 800-1000 rpm;

cooling and stirring time: 0.5 to 1 hour.

In the cannabidiol cream provided by the invention, vaseline, paraffin and liquid paraffin are high-quality oil phase matrixes, are chemically stable and have no irritation, and a proper amount of hexadecanol, octadecanol and fatty glyceride are added in the oil phase, so that the greasy feeling of the cream applied to the skin can be reduced. Meanwhile, the cannabidiol is a fat-soluble medicine, and the solubility and the stability of the cannabidiol can be improved by the existence of the oil phase. The skin moisturizer such as isopropyl myristate, isopropyl palmitate and dimethyl silicone oil can play a role in moisturizing skin, has good skin absorbability, and can effectively contact hair follicles in cortex. Is easy to be absorbed by skin. Cannabidiol is not very stable in solution, is easily oxidized to quinone in the presence of alkali and air, and is easily converted to the other cannabinoid-THC under strongly acidic conditions. Therefore, it is necessary to add suitable stabilizers (pH regulators, antioxidants) to the cream to ensure stability of cannabidiol. The medium and weak acidic environment condition is suitable for the preservation of cannabidiol, citric acid and ascorbic acid can provide the medium and weak acidic environment condition, and tocopherol and BHT are effective antioxidants. The moisturizing agents such as glycerin, propylene glycol, urea, amino acid and the like can adsorb moisture in the air, moisturize the skin and provide a moisturizing effect. White vaseline, paraffin and the like in the oil phase are insoluble in water, so that a protective film can be formed on the skin, the loss of skin moisture is prevented, and the functions of moisturizing and moistening the skin are achieved. Cannabidiol has been shown to bind to cannabinoid receptors (CB1/CB2) and arene receptors (AhR), thereby inhibiting the release of inflammatory factors and acting to inhibit inflammation. The cannabidiol cream has a large amount of CB1/CB2 and AhR in the skin, can make cannabidiol enter the local part of the skin and accumulate in different layers of the skin, and improves the concentration of the cannabidiol in the skin, so that the cannabidiol can inhibit the local inflammatory reaction, thereby treating inflammatory skin diseases. In addition, the moisturizer and the emollient in the cream can provide moisturizing and moisture-keeping effects, so that the barrier function of the skin is repaired, and the treatment of inflammatory skin diseases is accelerated.

The cream provided by the invention can provide high-concentration accumulation of cannabidiol in local skin, does not enter blood circulation basically, and is suitable for local application of skin diseases.

The cannabidiol cream provided by the invention has the advantages that raw materials, auxiliary materials and reagents used in the preparation method and the application of the cannabidiol cream can be purchased from the market.

The terms:

CBD, Cannabidiol, Cannabidiol

Atopic dermatitis, AD Atopic dermatitis;

contact demattitis: contact dermatitis;

neurodematitis: neurodermatitis;

seborroic dermatitis: seborrheic dermatitis

Allergic dematitis: allergic dermatitis

Acne, Acne

Cream Cream/Cream

LogP lipid water partition coefficient

Oleique CC 497: polyglycerol oleate

Transcutol P: diethylene glycol monoethyl ether

Labrasol polyethylene glycol caprylate capric acid glyceride

Butyl-related hydroxyurea, BHT: butylated hydroxytoluene

Butylated hydroxyanisole, BHA:butylatedhydroxyanisole

rpm is the rotational speed per minute

The invention is further illustrated by the following examples:

example 1:

name (R)	Weight, g
		Cannabidiol	8.7
Glyceryl monostearate	14.4
		Cetyl alcohol	20.6
White vaseline	20.5
		Stearic acid	5.8
Benzyl alcohol	0.1
		Glycerol	5.8
Isopropyl myristate (IPM)	0.9
		Citric acid	0.8
Water (W)	20

According to the formula, the cream is prepared according to the following preparation method:

(1) preparing an oil phase: the adjuvants as oil phase were weighed and added to a suitable beaker. The auxiliary materials used as the oil phase comprise an oil phase matrix, an emollient, an emulsifier and a preservative. After mixing, heating the oil phase to 60-80 ℃ to completely dissolve, and stirring uniformly at 900-1200 rpm.

(3) Preparing a water phase: the adjuvants are weighed as an aqueous phase and added to a suitable beaker. The water phase auxiliary material includes water, stabilizer, humectant glycerin. After mixing, heating the water phase to the same temperature (60-80 ℃) as the oil phase to completely dissolve the water phase, and uniformly mixing.

Example 2:

name (R)	Weight, g
		Cannabidiol	8
Polysorbate 80	4.4
		Stearic acid	2
White spiritForest (forest)	10
		Light liquid paraffin	5
TranscutolP	4.1
		Glycerol	6.48
Isopropyl myristate	15
		Citric acid	5
Nipagin ethyl ester	0.02
		Water (W)	40

(1) preparing an oil phase: the adjuvants as oil phase were weighed and added to a suitable beaker. The adjuvant used as oil phase comprises oil phase matrix, emollient, emulsifier, and antiseptic (such as benzyl alcohol, methyl hydroxybenzoate, ethylparaben, propylparaben, and phenethyl alcohol). After mixing, heating the oil phase to 60-80 ℃ to completely dissolve, and stirring uniformly at 900-1200 rpm.

(3) Preparing a water phase: the adjuvants are weighed as an aqueous phase and added to a suitable beaker. The adjuvants for the water phase include water phase solvent, stabilizer (water soluble adjuvants such as citric acid and ascorbic acid), and humectant glycerol. After mixing, heating the water phase to the same temperature (60-80 ℃) as the oil phase to completely dissolve the water phase, and uniformly mixing.

Example 3:

name (R)	Weight, g
		Cannabidiol	2.85
Glyceryl monostearate	10
		White vaseline	25
PlurololeiqueCC497	3
		TranscutolP	4
Propylene glycol	5.5
		Isopropyl myristate	0.7
Water (W)	15

(1) preparing an oil phase: the adjuvants as oil phase were weighed and added to a suitable beaker. The auxiliary materials used as the oil phase comprise an oil phase matrix, an emollient and an emulsifier. After mixing, heating the oil phase to 60-80 ℃ to completely dissolve, and stirring uniformly at 900-1200 rpm.

(3) Preparing a water phase: the adjuvants are weighed as an aqueous phase and added to a suitable beaker. The water phase auxiliary material includes water phase solvent, stabilizer and humectant glycerin. After mixing, heating the water phase to the same temperature (60-80 ℃) as the oil phase to completely dissolve the water phase, and uniformly mixing.

Example 4:

name (R)	Weight, g
		Cannabidiol	10
Polysorbate 80	11.7
		Stearic acid	14.3
White vaseline	17.4
		Light liquid paraffin	5.6
Glycerol	5.1
		Isopropyl myristate	1
TranscutolP	5
		Citric acid	1
Benzyl alcohol	1
		Water (W)	27.9

Example 5:

name (R)	Weight, g
		Cannabidiol	1
Polysorbate 80	11.7
		Stearic acid	17.4
White vaseline	6.6
		Glyceryl monocaprylate	14.3
Benzyl alcohol	0.1
		Propylene glycol	8.2
Dimethyl silicone oil	4.3
		TranscutolP	0.5
Sodium chloride	0.1
		Citric acid	0.1
Water (W)	27.9

(3) Preparing a water phase: the adjuvants are weighed as an aqueous phase and added to a suitable beaker. The water phase auxiliary material includes water phase solvent, stabilizer and humectant propylene glycol. After mixing, heating the water phase to the same temperature (60-80 ℃) as the oil phase to completely dissolve the water phase, and uniformly mixing.

Example 6:

Example 7:

Example 8:

name (R)	Weight, g
		Cannabidiol	5
Light liquid paraffin	32
		White vaseline	12
Stearic acid	5
		Glyceryl monostearate	14.8
Benzyl alcohol	0.1
		Glycerol	15
Isopropyl myristate	2
		Sodium chloride	0.1
LemonAcid(s)	1
		Span 80	1
Plurol Oleique CC 497	2
		Water (W)	10

Example 9:

name (R)	Weight, g
		Cannabidiol	5
Mineral oil	22
		White vaseline	22
Stearic acid	14.8
		Phenylethanolic acid	0.1
Glycerol	15
		Palmitic acid isopropyl ester	7
BHT	1
		Span 20	1
PEG-40 stearate	2
		Propylene glycol	10

(4) Emulsification: and slowly adding the water phase (not more than 20ml/min) into the oil phase under the conditions of heating to 60-80 ℃ and stirring until the water phase is completely added, rotating at 900-1200 rpm, and stirring for 20-60 minutes at 60-80 ℃. And taking the emulsion off from the heating state, placing the emulsion in a temperature of 25 +/-5 ℃, continuously stirring, naturally cooling the emulsion in the stirring state, wherein the stirring speed of cooling is 800-1000 rpm, and stopping stirring after 0.5-2 h to obtain the cream.

Effect example 1 in vitro Release test

The vertical transdermal diffusion instrument is used for detecting the in vitro release degree. After the vertical transdermal diffusion apparatus was assembled, 40% PEG400-PBS phosphate buffer (pH7.4) was added to the receptor cell as a receptor solution. Selecting a proper inert filter membrane, covering the upper part of a receptor pool, covering a quantitative ring on the filter membrane, taking 20-50 mg of the cream of the embodiment 4 and the cream serving as the comparative oil-in-water cream, spreading the cream on the quantitative ring, leveling, weighing, and recording the weight difference before and after the weight difference is used as the total dosage of the loading medicine. The sample is placed on a filter membrane on a receptor pool, and the beginning of the experiment is recorded, and when 0.5h,1h,1.5h,2h,2.5h,3h,4h,5h and 6h are carried out, the sample is respectively placed on the receptor pool0.6ml of medium is aspirated and made up to the mark with fresh 40% PEG400-PBS phosphate buffer. Drug release samples were taken at different time points and checked by HPLC. The water bath temperature is 32 +/-1 ℃, the stirring speed of the stirrer is 300rpm, the volume of the receptor pool is 12ml, and the circular hole areas of the donor pool and the receptor pool are 1.767cm²。

TABLE 1 in vitro Release raw data and calculation of Release Rate for cannabidiol cream in different emulsification systems

Figure 1 is a comparison of the in vitro release rate of cannabidiol creams of different emulsification systems at different time points. Table 1 is the raw data of picture 1 and the calculation of in vitro release rate, which is the slope after linear fitting. From the curve fitted in FIG. 1, it can be seen that when cannabidiol is formulated as a water-in-oil cream, the in vitro release rate is 52.24 μ g/cm²/h¹ ^/2By comparison, the in vitro release rate of the oil-in-water type is 8.76. mu.g/cm²/h^1/2Water-in-oil creams release much faster in vitro than oil-in-water creams.

In addition, t-test was performed based on the above data, and 017-191112A and 017-191112B had very significant difference at each time point, and the P value was less than 0.01. The P values of 0.5h,1h,2h,3h,4h and 6h are 0.000516 and 6.81 x 10 respectively^-6，9.65*10^-8，1.82*10^-7，8.45*10^-8，6.18*10^-8.

Since the drug must be released from the formulation before entering the skin, the in vitro release rate is an important quality parameter for the quality of the cream. The cream of the invention is water-in-oil type, and the in vitro release speed of the medicine is far faster than that of oil-in-water type.

Effect example 2 in vitro skin Permeability measurement

The vertical transdermal diffusion instrument is used for detecting the transdermal penetration speed in vitro. After the vertical transdermal diffusion apparatus was assembled, 47.5% ethanol-PBS phosphate buffer (ph7.4) was added to the receptor cell as a receptor solution. Taking the complete back skin of the Bama miniature pig, and taking out the skin of the pig by using an electric skin taking machine, wherein the thickness of the electric skin taking machine is set to be 0.64 mm. Placing a quantitative ring on the taken skin, taking 20-50 mg of the creams of the examples 1 and 7, adding the creams into the quantitative ring in the donor pool, trowelling, weighing, and recording the weight difference before and after the cream is taken as the total dosage of the loading medicine. The dosing ring was then covered with skin over the receptor well and covered with a glass plate. And clamping and fixing the donor pool and the receptor pool by using a clamp, and filling the receptor pool with the receptor solution to the scale mark to ensure that no air bubbles exist.

The start of the experiment was recorded and after 24h,48h 0.6ml was aspirated from the recipient pool as a permeant sample and checked by HPLC. After the transdermal experiment, the cannabidiol cream remained on the surface of the skin is wiped off by using a paper towel and 95% ethanol, the stratum corneum is repeatedly peeled off by using a transparent adhesive plaster for 5 times, the adhesive plaster is put into 10ml of methanol to be used as a stratum corneum sample, the skin of the epidermis is scraped off to separate from the dermis, and 10ml of methanol is respectively added. The methanol solution of each layer of skin is extracted under ultrasound for 30min to obtain residual solution of the drug in each layer of skin, and the residual solution is filtered at 0.45 μm and tested by HPLC.

In the permeability experiment, the water bath temperature of the diffusion pool is 32 +/-1 ℃, the stirring speed of the stirrer is 300rpm, the volume of the receptor pool is 12ml, and the cross-sectional areas of the circular holes of the donor pool and the receptor pool are 1.767cm²。

TABLE 2 amount of CBD penetrating the pigskin after 48h of penetration test and the residual amount in each layer of skin

Assuming that the skin thickness is 0.5mm, the residual data in the skin can be converted into a molar concentration (molar concentration: drug residual amount μ g cm)^-2*1cm²/314g*mol^-1/1cm²0.05cm), see table 4 below, studies have shown that CBD modulates IELs by binding AhR, where CBD requires 10 for activation of AhR³～10⁸pM (0.1-0.1 mM), therefore, the technology can completely transport CBD with enough quantity to activate AhR to generate immune response, thereby playing an anti-inflammatory role.

TABLE 3 residual molarity of the layers of skin

FIG. 2 shows the comparison of the amount of CBD cream that permeated into the skin and the residual amount after 48h of in vitro porcine skin permeation experiment on a vertical transdermal diffusion cell model. Table 2 is the raw data of fig. 1. The results of the 3 batches of creams show that the CBD drug amount in each layer of the skin is far larger than the amount penetrating the skin (017-191119B batches: 294.7> 43.0; 017-191219C batches: 382.3> 19.0; 017-191219C-2 batches: 338>37.3), and the t-test P value is smaller than 0.05(017-191119B: 0.000495; 017-191219C: 0.011849; 017-191219C-2: 0.027461), which have significant differences. Thus, when cannabidiol cream is applied to the skin, the proportion of the amount of drug that penetrates into the body is small (three batches of transdermal drug account for 12.7%, 4.7% and 9.9% of the total absorption), with a large amount of drug remaining on the skin, with the dermal layer being the largest. Under the technical scheme, the cannabidiol is accumulated locally on most of the skin, only a small part of the cannabidiol penetrates through the skin to enter the blood circulation, so that systemic side effects are reduced, and the cannabidiol is suitable for treating local skin diseases.

Effect example 3 drug residues in different skin layers after whole skin administration of Bama miniature pigs

After the small bama pigs were anesthetized to death, the whole back skin, including the lower fat layer, was removed. Cutting out the whole pigskin with a diameter of 2.54cm, uniformly smearing 50mg of cannabidiol cream of example 7 on the cut whole pigskin, incubating in a constant temperature shaking table at 32 deg.C for 5min,10min,15min,30min,1h, and 4h, taking out, and wiping the cream on the pigskin with 95% ethanol and paper towel. The skin was attached to a transparent adhesive tape, and then peeled off, and a part of stratum corneum was peeled off from the peeled adhesive tape, and this operation was repeated five times with the transparent adhesive tape, and the peeled adhesive tape was extracted in 10ml of methanol to obtain a stratum corneum residual sample.

The skin after the horny layer was peeled off was soaked in hot water at 60 ℃ for 1min, then the epithelial layer was scraped off with a scalpel, and the skin was extracted in 10ml of methanol to obtain a sample of the skin epithelial layer residue.

The skin after removing the stratum corneum and the epidermis layer, along with the fat, was extracted in 10ml of methanol as a residual sample of the dermal layer of the skin.

The extraction method comprises the following steps: and (4) carrying out ultrasonic treatment for 30min, filtering the extract liquor by using a 0.45-micrometer filter membrane after the ultrasonic treatment is finished to obtain an extracted sample, and detecting by using HPLC.

TABLE 4 raw data of skin residue at different time points after administration of whole pig skin

Figure 3 depicts the residual drug levels in the various layers of the skin at various time points following administration of cannabidiol cream to whole pigskin. The CBD residue of the CBD cream at each time is far higher than that of the mineral oil solution, the t-test P value is less than 0.05, and the significant difference exists, which indicates that the cream produced under the technical condition can improve the skin entering amount compared with the CBD mineral oil solution.

The data of the sum of the skin layers of the CBD cream at different time points are subjected to one-factor anova, the total amount of skin residues at different time points can be found to have very significant difference, the P value is 0.000961 and is less than 0.01, but the data of 30min,1h and 4h are extracted separately and subjected to anova, the P value is 0.096325 and is more than 0.05, and the data of the skin residues at 30min,1h and 4h are found to have no significant difference. Thus, it is believed that the drug, after administration, rises with increasing time, peaking at 15 min; then slightly decreases, but keeps stable within 30min-4h and maintains a certain level.

TABLE 5 drug residue data for different parts of pigskin

Figure 4 depicts the amount of drug that entered each layer of the skin with cannabidiol cream in different areas of the skin, and table 4 is the raw data. The data of the sum of the two groups of layers entering the skin are subjected to a t test, the P value is 0.056958 and is more than 0.05, and the P value do not have significant difference, which shows that the data have no statistical significance although the abdominal skin is higher. Thus, the cream was applied to the skin on the back or abdomen with no significant difference.

TABLE 6 drug residue data for creams of different concentrations

Figure 5 depicts the effect of cannabidiol cream concentration on the amount of residual drug that entered each layer of the skin. The results indicated that the CBD penetrated more into the skin at higher concentrations and the t-test results of the data summed over the two layers showed P values of 0.00095, less than 0.01, indicating that the data were very significantly different and statistically significant. This demonstrates that the high concentration of cannabidiol cream provided higher levels of residual skin content with this technique.

Effect example 4 stability data

Placing the produced cream in a constant temperature and humidity stability test box with the conditions of 25 +/-1 ℃ and 60% relative humidity, taking out after 1 month, observing the color change of the cream, detecting the pH value, content, viscosity, phase stability after centrifugation and the like, and comparing the data with the data of 0 day.

Color: observing with naked eyes;

the pH value measuring method comprises the following steps: suspending 1g of the cream in 10ml of water, mixing, and measuring the pH value by using a pH meter;

the content is as follows: precisely weighing a small amount (about 0.1g) of the cream, adding into 100ml of methanol, ultrasonically extracting for 30min, taking 1ml of the extract, diluting by 10 times, filtering with a 0.45-micron filter membrane, and introducing into HPLC for content determination. HPLC type: a seemer fly Ultimate 3000; a chromatographic column: agilent Zorbax SB C-18,5 μm,4.6 x 150 mm; the liquid phase method comprises the following steps: phase A is acetonitrile, phase B is water (containing 0.05% TFA), 0-10min, 22% B isocratic elution.

Viscosity: the viscosity was determined on Brookfield DV2T, rotor number 6, 50 rpm.

Crystal: and (5) observing with naked eyes.

Centrifugal phase stability: taking a small amount of cream, placing in a 1.5mL centrifuge tube, centrifuging at 4000rpm for 10min, and observing with naked eyes whether the two phases are separated after centrifugation.

TABLE 7 Effect of citric acid on stability

Table 7 describes the stability studies with and without citric acid added to the cream. Without the addition of citric acid, the pH of the cream was high, about 6.5, and after the addition of citric acid, the pH was about 3.0. This pH had a major impact on the stability of the CBD cream.

From the results it can be seen that the cream without citric acid changes colour from milky to light earthy yellow within a month, but that the colour does not change within a month after the addition of citric acid.

In addition, without the addition of citric acid, the CBD content decreased slightly after one month (content data t test P values of 0 and 1 month of 0.003416, less than 0.05, with significant differences); however, after citric acid is added as a stabilizer, the color is unchanged within one month (the P value of the content data t test of 0 month and 1 month is 0.4627 and is more than 0.05, and no significant difference exists), which indicates that the stabilizer citric acid can adjust the pH value of the cream and finally improve the stability of the CBD.

TABLE 8 stability data for the cream of example 8

Table 8 describes the 2 month stability results for the CBD cream formulated in example 8 at 25 ℃. The results show that after 2 months the pH increased from 3.63 to 4.66 at day 0, but the cream showed no change in properties, no visible crystals were produced, a level of 5.980, and no degradation compared to day 0, indicating that the major ingredient was stable. After 2 months, the viscosity of the sample is reduced to a certain extent compared with the viscosity of the sample in 0 day, but in a centrifugal phase stability experiment mainly judging the stability of the emulsifying system, two phases of the sample are still stable after centrifugation at 4000rpm, and no layering phenomenon exists, which indicates that the sample emulsifying system is still stable.

The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.

Claims

1. The cannabidiol cream is characterized by being water-in-oil cream and comprising the following components in parts by weight:

the emulsifier comprises:

2. The cannabidiol cream of claim 1, further comprising a combination of one or more of a penetration enhancer, a preservative, a stabilizer;

the adhesive comprises the following components in parts by weight:

3. the cannabidiol cream of claim 2, wherein the penetration enhancer comprises Transcutol P, Labrasol,

4. A cannabidiol cream as claimed in any one of claims 1 to 3 wherein the emulsifier has an HLB value of 4 to 8.

5. The cannabidiol cream of claim 4, comprising the following components in weight percent:

。

6. the cannabidiol cream of claim 5, comprising the following components in weight percent:

or

Or

Or

Or

Or

Or

Or

Or

。

7. A process for the preparation of cannabidiol cream as claimed in any one of claims 1 to 6 comprising the steps of:

step 1: preparing oil phase, mixing oil phase matrix, emulsifier, emollient, penetration enhancer (such as transcutol P), antiseptic, heating to 60-80 deg.C for melting, and dissolving cannabidiol in oil phase;

step 2: preparing a water phase, mixing auxiliary materials in the water phase, including a water phase solvent, a humectant and a stabilizer, and heating to 60-80 ℃;

and 4, step 4: and (3) placing the mixture at the temperature of 25 +/-5 ℃, cooling the mixture and continuously stirring the mixture for 0.5 to 1 hour at the rpm of 800 to 1000 to obtain the emulsifiable paste.

8. The method according to claim 7, wherein the rotation speed of the emulsification is 900 to 1200rpm, and the time of the emulsification is 20 to 60 min.

9. The method according to claim 7 or 8, wherein the stirring speed of the cooling is 800 to 1000rpm, and the stirring time of the cooling is 0.5 to 1 hour.

10. Use of cannabidiol cream as claimed in any one of claims 1 to 6 or as prepared by the process of any one of claims 7 to 9 in the manufacture of a medicament for the treatment and/or prophylaxis of a skin disorder.