Composition for external use on skin

Abstract

The invention provides an external skin preparation which contains montmorillonite, sodium hyaluronate and other necessary auxiliary materials. The traditional Chinese medicine composition has clinical application value in treatment of atopic dermatitis, such as eczema, baby diaper dermatitis and the like.

Description

Technical Field

[0001] The invention relates to the field of skin medicinal compositions, in particular to an external lotion composition containing montmorillonite. Background Art

[0002] Clinically, montmorillonite is used for acute and chronic diarrhea in adults and children. The main dosage forms that have been launched on the market are montmorillonite powder, montmorillonite suspension, montmorillonite granules, etc., all of which are oral preparations. Its pharmacological effects are as follows: montmorillonite has a layered structure and non-uniform charge distribution, and has a strong fixation and inhibition effect on viruses, bacteria and toxins and gases produced in the digestive tract, making them lose their pathogenic effects; in addition, it also has a strong covering and protective ability for the digestive tract mucosa, repairs and improves the defense function of the mucosal barrier against attacking factors, and has the effect of balancing normal flora and local analgesia.

[0003] In addition, a number of clinical application studies have shown that applying montmorillonite powder to the affected area or mixing it with an appropriate amount of saline to form a paste and applying it to the affected area has a very significant effect on the treatment of diaper dermatitis and eczema in infants and young children.

[0004] In summary, developing montmorillonite as a topical pharmaceutical preparation for the treatment of atopic dermatitis has significant clinical value.

[0005] Currently, all montmorillonite preparations on the market are oral preparations. Montmorillonite powder can be used externally, but it is not easy to adhere to the skin and has a poor therapeutic effect. When used clinically, it needs to be temporarily prepared into a paste with normal saline or purified water, which is very inconvenient to use.

[0006] In order to meet clinical needs, it is necessary to develop an external preparation containing montmorillonite that has good clinical effects and is easy to use. Summary of the invention

[0007] In order to solve one of the above technical problems existing in the prior art, the present invention provides an external skin preparation containing montmorillonite. Furthermore, the present invention also provides the purpose and use method of the preparation.

[0008] According to one aspect of the present invention, a topical skin preparation is provided, which includes: montmorillonite, sodium hyaluronate, and a suspending agent. The amount of montmorillonite is 20-30% (w / w), the amount of sodium hyaluronate is 0.01-0.1% (w / w), and the amount of the suspending agent is 0.1%-1.0% (w / w). Montmorillonite is a white, grayish white or light yellow powder, the main component of which is silicate. It has strong oil absorption and adsorption capacity, can absorb excess oil and dirt on the skin surface, and promote skin self-repair. Sodium hyaluronate has the function of moisturizing and promoting penetration in the preparation, and also has the function of a stabilizer. The suspending agent is very important for meeting the quality of the product. Without the suspending agent, the sedimentation ratio and adhesion of the liquid do not meet the quality requirements.

[0009] According to one embodiment of the present invention, the particle size of montmorillonite is D 50 20~40μm. The particle size of montmorillonite will affect the stability of the product.

[0010] According to one embodiment of the present invention, the suspending agent can be selected from one or more of the following substances: sodium carboxymethylcellulose, povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol 4000, and polyethylene glycol 6000. When the suspending agent is sodium carboxymethylcellulose, its dosage is 0.1% to 1.0% (w / w).

[0011] According to one embodiment of the present invention, the topical skin preparation may further include a pH regulator selected from one or more of the following combinations: citric acid-sodium citrate, acetic acid-sodium acetate, and carbonic acid-sodium bicarbonate. When the pH regulator is citric acid-sodium citrate, the dosage is 0.1-1.0% (w / w) of citric acid and 0.2-2% (w / w) of sodium citrate.

[0012] According to one embodiment of the present invention, the topical skin preparation may further include a preservative selected from one or more of the following substances: methylparaben, propylparaben, sodium benzoate, sorbic acid, benzalkonium chloride. When the preservative is a combination of methylparaben and propylparaben, the amount used is 0.015-0.2% (w / w) of methylparaben and 0.01-0.1% (w / w) of propylparaben.

[0013] According to one embodiment of the present invention, the topical skin preparation may further include a moisturizer selected from one or more of the following substances: glycerol, propylene glycol, sorbitol and derivatives thereof. The preferred moisturizer is glycerol in an amount of 5-10% (w / w).

[0014] The external skin preparation provided by the present invention belongs to the type of lotion and has outstanding curative effect in treating atopic dermatitis, especially has good application prospect in treating eczema and infant diaper dermatitis.

[0015] The topical skin preparation provided by the present invention has the following advantages in clinical use:

[0016] 1. Sodium hyaluronate is used in combination with montmorillonite. The former can promote the absorption of the product and improve the clinical effect.

[0017] 2. The external skin preparation provided by the present invention has good suspension stability and adhesion and is easy to apply during clinical use.

[0018] 3. It can be used well to treat atopic dermatitis, such as eczema.

[0019] 4. It is highly safe and easy to use. It can be used for children's skin diseases, such as baby diaper dermatitis. DETAILED DESCRIPTION

[0020] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with embodiments. The specific embodiments described herein are only used to explain the present invention and are not intended to constitute any limitation of the present invention. In addition, in the following description, the description of known structures and technologies is omitted to avoid unnecessary confusion of the concepts of the present disclosure. Such structures and technologies are also described in many publications.

[0021] definition

[0022] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as commonly used in the field to which the present invention belongs. For the purpose of interpreting this specification, the following definitions will apply, and where appropriate, terms used in the singular will also include the plural form, and vice versa.

[0023] Unless the context clearly dictates otherwise, the expressions "a", "an" and "an" as used herein include plural references. For example, reference to "a cell" includes a plurality of such cells and equivalents thereof known to those skilled in the art, and so forth.

[0024] As used herein, the term "about" refers to a range of ±20% of the value that follows. In some embodiments, the term "about" refers to a range of ±10% of the value that follows. In some embodiments, the term "about" refers to a range of ±5% of the value that follows.

[0025] Examples are provided below to help understand the present invention. However, it should be understood that these examples are only used to illustrate the present invention, but do not constitute any limitation. The actual scope of protection of the present invention is set forth in the claims. It should be understood that any modifications and changes can be made without departing from the spirit of the present invention. The reagents and / or kits used in the following examples are all commercially available or can be synthesized by known methods.

[0026] It should be noted that, if the specific conditions are not specified in the examples, the experimental conditions are carried out according to conventional conditions, manufacturer recommendations or publicly reported experimental conditions. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially. If the manufacturer of the reagents used is specified, similar products from other manufacturers are substitutable.

[0027] Preparation example:

[0028] The external skin preparation provided by the present invention is prepared according to the prescription composition shown in Table 1 below.

[0029] Weigh 2 / 3 of the prescribed amount of purified water into a container, heat and control the temperature to 70-80°C, add the prescribed amount of sodium hyaluronate, preservatives, and pH adjusters and stir until completely dissolved; disperse the suspending agent in the moisturizer, then add it to the drug solution, stir until completely dissolved, then add montmorillonite, stir for not less than 10 minutes to evenly disperse, stop heating and cool to room temperature; add water until sufficient amount and stir evenly to make a montmorillonite suspension.

[0030] Table 1 Prescription composition and dosage (w / w)

[0031]

[0032]

[0033] Example 1: Quality Evaluation

[0034] 1. Sedimentation volume ratio

[0035] This lotion product is a suspension. The 2020 edition of the Chinese Pharmacopoeia stipulates under "0127 Lotion" that "if a precipitate appears in the suspension, it should be easily dispersed by shaking and have sufficient stability to ensure the accuracy of the dosage." The stability evaluation method after dispersion refers to the determination method of sedimentation volume ratio under "0123 Oral solution, oral suspension, oral emulsion":

[0036] [Sedimentation Volume Ratio] The oral suspension should be inspected according to the following method. The sedimentation volume ratio should not be less than 0.90.

[0037] Inspection method Unless otherwise specified, use a stoppered measuring cylinder to measure 50 ml of the test sample, stopper it tightly, shake it vigorously for 1 minute, record the initial height H0 of the suspension, let it stand for 3 hours, record the final height H of the suspension, and calculate it according to the following formula:

[0038] Sedimentation volume ratio = H / H0

[0039] Dry mixed suspension should be evenly dispersed by adding water and shaking according to the proportion specified under each variety, and the sedimentation volume ratio should be checked according to the above method, which should comply with the regulations.

[0040] It has been determined that the sedimentation ratio of the external preparations provided by the present invention is ≥0.90, which meets the requirements of the pharmacopoeia, and the preferred solution is not less than 0.95.

[0041] 2. Skin Adhesion

[0042] The composition provided by the present invention is an external lotion, which should have good adhesion after being applied to the affected part of the skin to ensure good medication effect.

[0043] Adhesion test method: Take 1 mL of the drug solution and apply it on a silicone plate with an area of ​​5 cm × 5 cm. Then lean the silicone plate against the wall at 45° and let it stand for 5 minutes. Observe the flow of the drug solution and evaluate the adhesion effect.

[0044] After testing, it was found that after the topical preparation was applied to the silicone plate, almost no liquid medicine flowed out of the wiped area, the adhesion was very good, and it met the pharmaceutical standards.

[0045] 3. Antibacterial effect

[0046] After testing, this product is a solution and a multi-dose preparation, and the antibacterial efficacy of the product should meet the requirements.

[0047] Table 2 is a summary of the quality test results of the prescriptions provided in the preparation examples of the present invention.

[0048] Table 2 Quality results of each prescription sample

[0049]

[0050] Example 2: Formulation Screening

[0051] 1. Test of quality indicators:

[0052] Prescriptions 1 and 2 in the preparation examples were selected as the test group, and comparative examples 1-6 were designed as the control group according to the prescription composition and proportion in Table 3 below.

[0053] Table 3 Composition and effect test of comparative examples

[0054]

[0055] The test group and the control group were tested for the corresponding quality indicators according to the method of Example 1. The test results are shown in Table 4.

[0056] 2. Therapeutic effect on eczema model mice

[0057] (1) Sample preparation

[0058] Test sample group 1: Take an appropriate amount of sample from recipe 3, which is the full recipe sample. Save for later use.

[0059] Test sample group 2: Take an appropriate amount of the sample of comparative example 5, i.e., the sample without sodium hyaluronate, and save it for later use.

[0060] Negative control group: pure water.

[0061] Positive control group 1: Compound dexamethasone acetate cream (999 Piyanping): batch number 1706004H.

[0062] Positive control group 2: Erfukang ointment (National Medicine Standard B20020017, Chengdu Senke Pharmaceutical Co., Ltd., batch number 170807), diluted 2 times with pure water.

[0063] (2) Test methods and operations

[0064] Study on the therapeutic effect of DNFB on mice with atopic dermatitis

[0065] Select male mice weighing 23-26 g, cut the hair on the abdomen and remove the hair on the back (depilatory cream) about 2×3 cm before the experiment. 2 Except for 11 animals randomly selected as the normal control group, the rest of the animals were sensitized by applying 50 μL of 2% DNFB acetone olive oil solution on the abdominal haircut with a pipette on the day after hair removal, and boosted once on the second day. The next day after the second sensitization, the model animals were randomly divided into 5 groups according to body weight: model control group; chemical drug control group; traditional Chinese medicine control group; test sample groups 1 and 2; each group had 11 animals. On the 5th and 8th day after the last sensitization, 50 μL of 0.5% DNFB mixture was applied to the depilatory area on the back to induce dermatitis in the animals of each model group, and 4 hours after the first stimulation, the depilatory area on the back and the inner and outer sides of both ears were evenly coated with the ointment: the normal and model control groups were given pure water (0.5 mL on the back, 50 uL per ear), the chemical drug control group was given Pi Yan Ping (10 mg on the back, 5 mg per ear), the Chinese medicine control group was given 2-fold diluted Erfu Kang ointment (0.5 mL on the back, 50 uL per ear), and the test sample groups 1 and 2 were given 5-fold diluted stock solution (0.5 mL on the back, 50 uL per ear); the drugs were administered once in the morning and afternoon every day for 8 consecutive days. 1 hour after the last administration, 30 uL of 0.5% DNFB acetone olive oil solution was applied to the right ear for stimulation, and the left ear was applied with the same amount of acetone olive oil solution as a control, and the right ear was applied with the ointment once again 6 hours later. 24 hours after the challenge, the mice were killed by dislocating the cervical vertebrae, and the ears of the same area were weighed with an 8mm diameter puncher. The difference in weight between the two ear pieces was used as the swelling index, and the swelling inhibition rate was calculated; the thymus and spleen were dissected and weighed, and the spleen and thymus coefficients were calculated; and the back skin of each group of animals was taken for pathological histological examination. The results are shown in Tables 5 and 6.

[0066] Swelling inhibition rate = (swelling degree of model group - swelling degree of drug administration group) / swelling degree of model group × 100%;

[0067] 2. Results and analysis

[0068] As shown in Table 4, the quality evaluation of prescriptions 1 and 2 provided by the present invention meets the requirements for clinical use.

[0069] Table 4 Quality comparison between the test group and the control group

[0070]

[0071] Comparative Example 1 shows that when the raw material particle size is large, the raw material in the liquid medicine is easy to settle, and the sedimentation ratio does not meet the quality requirements.

[0072] Comparative Example 2 shows that when the particle size of the raw material montmorillonite is very small, the liquid medicine is in a viscous paste state, which does not meet the property standard of the lotion. Similarly, Comparative Example 3 shows that if the amount of raw material montmorillonite is large, the liquid medicine also presents a viscous paste state, which does not meet the property standard.

[0073] From the results of Comparative Example 4, it can be seen that when the amount of raw material montmorillonite is very small, the sedimentation ratio does not meet the quality requirements and the adhesion of the liquid medicine is also poor compared with prescriptions 1 and 2. Similarly, the test results of Comparative Example 6 show that when there is no suspending agent, the liquid medicine properties, sedimentation ratio and adhesion also do not meet the requirements.

[0074] Table 5 Effects on ear swelling and immune organs of model mice

[0075]

[0076] Compared with the control group, △ / △△p<0.05 / 0.01; compared with the model group, * / **P<0.05 / 0.01

[0077] As shown in Table 5, the ear swelling and spleen coefficient of the model group mice were significantly higher than those of the normal control group; compared with the model group, each drug group could significantly inhibit the ear swelling of mice induced by DNFB and significantly reduce the spleen coefficient after continuous topical application for 8 days; and reduce the thymus coefficient to varying degrees. The order of ear swelling inhibition: Piyanping > test sample 1 > Erfukang > test sample 2.

[0078] Table 6: Effects on skin histopathology in model mice

[0079]

[0080] In summary, compared with the group without sodium hyaluronate, the topical preparation of the combination of montmorillonite and sodium hyaluronate had a significant improvement on the skin pathological changes in the atopic dermatitis model mice, indicating that the test sample of the pharmaceutical composition with the addition of sodium hyaluronate had a better repair effect on the skin damage of eczema mice.

[0081] The technical solution of the present invention is not limited to the above-mentioned specific embodiments. All technical variations made according to the technical solution of the present invention fall within the protection scope of the present invention.

Claims

1. A skin preparation for external use, comprising: Montmorillonite, sodium hyaluronate, and a suspending agent, wherein the amount of the montmorillonite is 20-30% (w / w), the amount of the sodium hyaluronate is 0.01-0.1% (w / w), and the amount of the suspending agent is 0.1%-1.0% (w / w).

2. The preparation as claimed in claim 1, wherein the particle size of the montmorillonite is D 50 20~40μm.

3. The preparation as claimed in claim 1, wherein the suspending agent is selected from one or more of the following substances: sodium carboxymethyl cellulose, povidone, hypromellose, hydroxypropyl cellulose, polyethylene glycol 4000, and polyethylene glycol 6000.

4. The preparation according to claim 3, wherein the suspending agent is sodium carboxymethyl cellulose in an amount of 0.1% to 1.0% (w / w).

5. The preparation as claimed in claim 1, further comprising a pH adjuster, selected from one or more of the following combinations: citric acid-sodium citrate, acetic acid-sodium acetate, carbonic acid-sodium bicarbonate.

6. The preparation according to claim 5, wherein the pH adjuster is citric acid-sodium citrate, and the dosage is 0.1-1.0% (w / w) citric acid and 0.2-2% (w / w) sodium citrate.

7. The preparation as claimed in claim 1, further comprising a preservative selected from one or more of the following substances: sodium benzoate, methylparaben, propylparaben, sorbic acid, benzalkonium chloride.

8. The preparation as claimed in claim 7, wherein the preservative is a combination of methylparaben and propylparaben, and the amount used is 0.015% to 0.2% (w / w) of methylparaben and 0.01% to 0.1% (w / w) of propylparaben.

9. The preparation according to claim 1, further comprising a humectant selected from one or more of the following substances: glycerol, propylene glycol, sorbitol and derivatives thereof, preferably glycerol in an amount of 5-10% (w / w).

10. The preparation according to claims 1-9, for use in treating atopic dermatitis, preferably, the atopic dermatitis is eczema or infant diaper dermatitis.

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