Application of rapamycin in preparing drugs for auxiliary treatment of coffee spots

Abstract

The present invention discloses the use of rapamycin in the preparation of a drug for the auxiliary treatment of coffee spots, and specifically relates to the field of medical technology. The content of rapamycin in the drug is 0.05% to 1%. The present invention finds that Q-switched laser combined with topical rapamycin topical preparation can significantly improve the therapeutic effect of coffee spots patients. The present invention can significantly improve the therapeutic effect and reduce the proportion of re-pigmentation by using the topical rapamycin topical preparation as an auxiliary for coffee spots patients who are ineffective or have no significant improvement with Q-switched laser treatment alone.

Description

Technical Field

[0001] The invention relates to the technical field of medicines, and in particular to application of rapamycin in preparing a drug for assisting in treating coffee spots. Background Art

[0002] Coffee-fronted spots (CALMs) are a common pigmented skin disease in children, with an incidence of about 10%-20%. The disease will not disappear naturally, and the area usually increases in proportion to age and physical development. When the lesions are located in exposed areas such as the face, it seriously affects the appearance of the child, especially during this special period of growth and development. Disfiguring diseases seriously affect the child's learning, social interaction, and physical and mental health. Currently, laser is the main treatment for this disease. Guidelines recommend Q-switched 755nm alexandrite laser (picosecond / nanosecond level), Q-switched 694nm ruby ​​laser (picosecond / nanosecond level), Nd:YAG Q-switched 532nm (picosecond / nanosecond level), Nd:YAG Q-switched 1064nm, 585nm-595nm dye laser, and intense pulsed light as treatment methods.

[0003] The efficacy of laser treatment alone is low and the recurrence rate is high, that is, the skin will re-pigment (blacken) after each treatment. For example, the efficacy of Q-switched alexandrite laser treatment is only about 50%, and the recurrence rate after treatment is as high as 20%-30%. Some patients are even resistant to laser treatment.

[0004] Rapamycin (RAP): Sirolimus is a macrolide immunosuppressant. It has been reported that RAP can block intercellular signal transduction and affect cell proliferation and differentiation by affecting multiple cell signaling pathways or different cytokines and related receptors. Currently, it has been reported that rapamycin can participate in the regulation of melanocytes and melanin synthesis. Some scholars have found that rapamycin intervention can reduce the formation of melanin granules in the development of clawed frog embryos, and mTOR inhibitors can inhibit the proliferation of melanocytes.

[0005] In clinical work, there are some patients with coffee-flavored spots who are ineffective or have no significant improvement after simple Q-switched laser treatment. How to improve the coffee-flavored spots of these patients has become a difficult problem that needs to be solved urgently. Summary of the invention

[0006] To this end, the present invention provides the use of rapamycin in the preparation of a drug for the auxiliary treatment of coffee spots, so as to solve the problem that the existing Q-switched laser alone is ineffective or has no significant improvement in the treatment of coffee spots.

[0007] In clinical work, the inventors found that for some patients with coffee spots that were ineffective or had no significant improvement with Q-switched laser treatment alone, the combined use of topical rapamycin preparations could significantly improve the treatment effect and reduce the proportion of repigmentation. Therefore, it is proposed that topical rapamycin preparations can be used as a combined topical drug for Q-switched laser treatment of coffee spots.

[0008] In order to achieve the above object, the present invention provides the following technical solutions:

[0009] According to one aspect of the present invention, there is provided use of rapamycin in the preparation of a drug for the auxiliary treatment of coffee spots.

[0010] Furthermore, in the drug, the content of rapamycin is 0.05% to 1%.

[0011] Furthermore, the drug includes rapamycin and common pharmaceutical excipients.

[0012] Furthermore, the commonly used pharmaceutical excipients are natural, semi-natural or fully synthetic.

[0013] The pharmaceutical excipients may be solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, adhesives, disintegrants and fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, integrators, penetration enhancers, pH regulators, buffers, plasticizers, surfactants, foaming agents, defoamers, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculating agents, filter aids, release retardants, etc.

[0014] Furthermore, the drug also includes a pharmaceutically acceptable carrier.

[0015] Furthermore, the coffee spots are patients for whom simple Q-switched laser treatment is ineffective or has no significant improvement.

[0016] Furthermore, the medicine is an ointment, granules, aqueous solution, suspension, plaster or gel.

[0017] According to another aspect of the present invention, a rapamycin external preparation is provided, wherein the preparation method of the external preparation is as follows: taking a sirolimus standard product, grinding it into 80-mesh powder in a mortar; taking yellow vaseline, heating it in a constant temperature water bath to dissolve it, heating it to 60° C., slowly adding the 80-mesh sirolimus powder, stirring while adding it, so that it is fully dispersed, and obtaining a rapamycin ointment.

[0018] The present invention has the following advantages:

[0019] 1. The present invention found that Q-switched laser combined with topical rapamycin topical preparation can significantly improve the therapeutic effect of patients with coffee spots.

[0020] 2. The present invention can significantly improve the treatment effect and reduce the proportion of repigmentation by auxiliary application of rapamycin topical preparations to patients with coffee spots that are ineffective or have no significant improvement with Q-switched laser treatment alone. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] In order to more clearly illustrate the implementation methods of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for the implementation methods or the description of the prior art. Obviously, the drawings in the following description are only exemplary, and for ordinary technicians in this field, other implementation drawings can be derived from the provided drawings without creative work.

[0022] The structures, proportions, sizes, etc. illustrated in this specification are only used to match the contents disclosed in the specification so as to facilitate understanding and reading by persons familiar with the technology. They are not used to limit the conditions under which the present invention can be implemented, and therefore have no substantial technical significance. Any structural modification, change in proportion or adjustment of size shall still fall within the scope of the technical contents disclosed in the present invention without affecting the effects and purposes that can be achieved by the present invention.

[0023] Figure 1 A comparison chart before and after treatment provided for Case 1 of the present invention; wherein A-one course of Q-switched laser treatment alone; B-two courses of Q-switched laser treatment alone; C-one course of Q-switched laser + topical rapamycin treatment;

[0024] Figure 2 A comparison chart before and after treatment provided for Case 2 of the present invention; wherein A-before treatment; B-two courses of treatment with Q-switched laser + topical rapamycin preparation;

[0025] Figure 3 A comparison chart before and after treatment provided for Case 3 of the present invention; wherein A-single Q-switched laser treatment for 1 course; B-Q-switched laser + rapamycin topical preparation treatment for 1 course; C-Q-switched laser + rapamycin topical preparation treatment for 2 courses;

[0026] Figure 4 A comparison chart before and after treatment provided for Case 4 of the present invention; wherein A-single Q-switched laser treatment for 4 courses; B-Q-switched laser + rapamycin topical preparation treatment for 1 course; C-Q-switched laser + rapamycin topical preparation treatment for 3 courses; D-Q-switched laser + rapamycin topical preparation treatment for 4 courses;

[0027] Figure 5A comparison chart before and after treatment provided for Case 5 of the present invention; wherein A-before treatment; B-single Q-switched laser treatment for 1 course; C-Q-switched laser + rapamycin topical preparation treatment for 1 course; D-Q-switched laser + rapamycin topical preparation treatment for 2 courses; E-Q-switched laser + rapamycin topical preparation treatment for 3 courses; F-Q-switched laser + rapamycin topical preparation treatment for 5 courses;

[0028] Figure 6 A comparison chart before and after treatment provided for Case 6 of the present invention; wherein A-before treatment; B-one course of treatment with Q-switched laser + topical rapamycin preparation;

[0029] Figure 7 A comparison chart before and after treatment is provided for Case 7 of the present invention; wherein A-before treatment; B-one course of treatment with Q-switched laser + topical rapamycin preparation. DETAILED DESCRIPTION

[0030] The following is a description of the implementation of the present invention by specific embodiments. People familiar with the art can easily understand other advantages and effects of the present invention from the contents disclosed in this specification. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0031] Sirolimus standard: The manufacturer is the New Drug Research and Development Center of North China Pharmaceutical Co., Ltd., and the batch number is YNSN1501401.

[0032] Drug preparation: Preparation of rapamycin ointment: Take sirolimus standard and grind it into 80 mesh powder in a mortar. Take yellow vaseline and heat it in a constant temperature water bath to dissolve it. Heat it to 60°C and slowly add sirolimus powder while stirring to fully disperse it.

[0033] Depending on the location of the coffee spot or the different therapeutic effects, different concentrations of rapamycin ointment can be selected, such as 0.1%, 0.2%, 0.3%, 0.4%, 0.5% and other concentrations. The concentration of 0.1% is preferably considered. If the treatment effect of 0.1% is not good, you can consider increasing its concentration.

[0034] The rapamycin drug dosage form can be prepared into solutions, gels, plasters and other preparations in addition to ointments, and can be applied externally to skin lesions.

[0035] Different options for lasers: You can choose Nd:YAG laser / Q-switched alexandrite laser, etc.; as well as lasers of different wavelengths (such as 755nm, 532nm, etc.).

[0036] The present invention combines the original laser treatment to remove pigment particles with rapamycin treatment to inhibit melanin synthesis, thereby better improving the treatment effect and reducing the repigmentation rate.

[0037] Example 1

[0038] 1. Drug preparation: Preparation of 0.1% rapamycin ointment: Take 1g of sirolimus standard and grind it into 80-mesh powder in a mortar. Take 1000g of yellow vaseline and heat it in a constant temperature water bath to dissolve it. Heat it to 60°C and slowly add sirolimus powder while stirring to fully disperse it.

[0039] 2. Instrument and equipment selection:

[0040] (1) Laser instrument: Q-switched laser (picosecond / nanosecond)

[0041] (2) Camera and photography: Canon 750D. The same camera was used for each visit, and the same dermatologist selected the same exposure intensity in the same consulting room and under the same light. The shooting angle was determined according to the child's cooperation.

[0042] (3) Rapamycin ointment: 0.1% rapamycin ointment was prepared by the Pharmacy Department of Children's Hospital according to the above-mentioned proportioning method and packaged.

[0043] 3. Intervention measures:

[0044] Patient treatment measures: Q-switched laser combined with topical 0.1% rapamycin ointment;

[0045] The patient was treated with Q-switched laser. About one week after the treatment, after the scab fell off naturally, a thin layer of rapamycin ointment was applied to the treated area. The topical medication was used until the next treatment. The interval between the two treatments was 8-12 weeks. The treatment effect is shown in Table 1.

[0046] Diagnostic criteria:

[0047] Café au lait spots, also known as cafe au lait spots, are diagnosed mainly based on clinical features. They are manifested as clearly demarcated pigmented spots that exist at birth or shortly after birth. They vary in shape and number, and range in size from a few millimeters to 20 cm or larger. They mostly occur on the face and trunk. A certain proportion of normal people may develop them, and certain diseases such as neurofibromatosis, tuberous sclerosis, and Albright syndrome may also be accompanied by café au lait spots.

[0048] Criteria for judging the efficacy of coffee spot treatment: Two doctors with a professional title of attending physician or above use the visual analogue scale (VAS) to evaluate the treatment effect. The efficacy is graded according to the internationally accepted four-level classification: Grade I, pigmentation reduction <25% (poor or ineffective); Grade II, pigmentation reduction 25%-49% (fair); Grade III, pigmentation reduction 50%-74% (good); Grade IV, pigmentation reduction ≥75% (significant).

[0049] Table 1 Statistical table of the efficacy of Q-switched laser combined with 0.1% rapamycin ointment in patients (previous laser treatment was ineffective)

[0050]

[0051] *No overlap between groups of patients

[0052] As shown in Table 1, 23 patients whose coffee spots were ineffective after laser treatment for 3 courses or more were treated with laser combined with external 0.1% rapamycin ointment, and the total effective rate of combined treatment (improvement ≥25%) was 95.65%, which was significantly higher than the effective rate of laser treatment alone (about 50%); in addition, 61.54% of the patients were significantly effective (improvement ≥50%) after less than 3 courses of combined treatment, and 100% of the patients were significantly effective after ≥3 courses of combined treatment, indicating that the efficacy is better as the number of combined treatments increases. Therefore, the present invention provides a new treatment method for treating coffee spots in clinical practice.

[0053] Example 2

[0054] Coffee spots that had not been treated with Q-switched laser in the past were initially treated with Q-switched laser combined with topical rapamycin preparations, which also achieved significant therapeutic effects.

[0055] In addition, during clinical diagnosis and treatment, Q-switched laser combined with rapamycin topical preparations were used to treat café-au-lait spots in some children with neurofibroma, but the therapeutic effect was much worse than that of children with simple café-au-lait spots. This shows that the treatment regimen of the present invention is only effective in treating simple café-au-lait spots.

[0056] Case 1

[0057] Female, 4 months old, had brown spots on the right cheek since birth; one course of Q-switched laser treatment alone, the color lightened by 10%; two courses of Q-switched laser treatment alone, the color lightening did not improve significantly, and re-pigmentation appeared; then Q-switched laser + rapamycin topical preparation treatment for one course, the color lightened by 75%; before and after treatment Figure 1 shown.

[0058] Case 2

[0059] Male, 5 years and 4 months old, with brown spots on the right cheek since birth. He was treated with Q-switched laser in another hospital for 2 courses, and the spots were restored after 1 week. Later, our hospital used Q-switched laser + rapamycin topical preparation for 2 courses, and the spots were lightened by more than 90%. The comparison before and after treatment is shown in the figure below. Figure 2 shown.

[0060] Case 3

[0061] Male, 4 years and 6 months old, with brown patches on the right cheek since birth. After one course of Q-switched laser treatment, there was no improvement. After one course of Q-switched laser + rapamycin topical preparation treatment, the color was lightened by 50%. After two courses of Q-switched laser + rapamycin topical preparation treatment, the color was lightened by 75%. Figure 3 shown.

[0062] Case 4

[0063] Female, 2 years and 4 months old, with brown spots on the left cheek and zygomatic region, which have been there since birth. After 4 courses of Q-switched laser treatment, the color was lightened by about 15%, after 1 course of Q-switched laser + rapamycin topical preparation treatment, the color was lightened by 30%, after 3 courses of Q-switched laser + rapamycin topical preparation treatment, the color was lightened by 50%, after 4 courses of Q-switched laser + rapamycin topical preparation treatment, the color was lightened by 90%. Figure 4 shown.

[0064] Case 5

[0065] Male, 3 years and 9 months old, with brown spots on the right forehead, upper eyelid, temporal and zygomatic regions, which he had since birth. After one course of Q-switched laser treatment, the color was lightened by 10%, after one course of Q-switched laser + rapamycin topical preparation treatment, the color was lightened by 25%, after two courses of Q-switched laser + rapamycin topical preparation treatment, the color was lightened by 50%, after three courses of Q-switched laser + rapamycin topical preparation treatment, the color was lightened by 75%, after five courses of Q-switched laser + rapamycin topical preparation treatment, the color was lightened by more than 90%. The comparison before and after treatment is as follows: Figure 5 shown.

[0066] Case 6

[0067] Female, 9 years old, brown patch on right cheek, Q-switched laser + rapamycin topical preparation treatment for 1 course, the color lightened by 50%, before and after treatment Figure 6 shown.

[0068] Case 7

[0069] Female, 10 months and 14 days old, with brown spots around the left mouth since birth, treated with Q-switched laser + rapamycin topical preparation for 1 course, the color was lightened by 75%, before and after treatment Figure 7 shown.

[0070] The present invention finds that Q-switched laser combined with topical rapamycin topical preparation can significantly improve the therapeutic effect of coffee spot patients. The present invention can significantly improve the therapeutic effect and reduce the proportion of re-pigmentation by auxiliary topical rapamycin topical preparation for coffee spot patients who are ineffective or have no significant improvement with Q-switched laser treatment alone.

[0071] Although the present invention has been described in detail above by general description and specific embodiments, it is obvious to those skilled in the art that some modifications or improvements can be made to the present invention. Therefore, these modifications or improvements made without departing from the spirit of the present invention all belong to the scope of protection claimed by the present invention.

Claims

1. The use of rapamycin in the preparation of a drug for treating coffee spots by combined Q-switched laser, characterized in that: The coffee stain is a simple coffee stain.

2. The use according to claim 1, characterized in that: In the drug, the content of rapamycin is 0.05% to 1%.

3. The use according to claim 1, characterized in that: The medicine comprises rapamycin and common pharmaceutical excipients.

4. The use according to claim 3, characterized in that: The commonly used pharmaceutical excipients are natural, semi-natural or fully synthetic.

5. The use according to claim 3, characterized in that: The medicament further includes a pharmaceutically acceptable carrier.

6. The use according to claim 3, characterized in that: The coffee spots are patients for whom simple Q-switched laser treatment is ineffective or has no significant improvement.

7. The use according to claim 1, characterized in that: The medicine is an ointment, granules, aqueous solution, suspension, plaster or gel.

8. The use according to claim 7, characterized in that: The preparation method of the ointment is as follows: taking a sirolimus standard product, grinding it into 80-mesh powder in a mortar; taking yellow vaseline, heating it in a constant temperature water bath to dissolve it, heating it to 60° C., slowly adding the 80-mesh sirolimus powder, stirring it while adding it, so that it is fully dispersed, and obtaining rapamycin ointment.

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