Method for treating systemic lupus erythematosus by using hydroxychloroquine soluble microneedle

Abstract

The invention provides a method for treating systemic lupus erythematosus through a hydroxychloroquine soluble microneedle, and relates to the field of lupus erythematosus treatment.The method comprises the steps that S100, a hydroxychloroquine (HCQ) soluble microneedle patch is prepared, a mixture of hyaluronic acid and polyvinyl alcohol (PVA) serves as a soluble matrix of the microneedle patch, hydroxychloroquine is evenly loaded in the matrix, and the height of the microneedle is 300-1000 micrometers; according to the application, the microneedle penetrates through the cuticle to directly deliver the hydroxychloroquine to the subcutaneous target region, the first-pass effect and whole body exposure of oral administration are avoided, the retina toxicity and gastrointestinal tract side effects of the hydroxychloroquine are reduced, the height of the microneedle is controlled to be 500-800 microns, the microneedle only penetrates through the epidermal layer and does not touch nerve endings, and painless administration is realized; a patient can operate by himself / herself without assistance of professional medical personnel, a cross-linked structure of hyaluronic acid and a PVA matrix can realize slow release of hydroxychloroquine, and a highly expressed hyaluronic acid receptor at a lupus erythematosus lesion site is targeted through anti-CD44 antibody modification.

Description

Technical Field

[0001] The present invention relates to the field of lupus erythematosus treatment, and in particular to a method for treating systemic lupus erythematosus with hydroxychloroquine soluble microneedles. Background Art

[0002] Systemic lupus erythematosus (SLE) is a chronic autoimmune disease, one of the symptoms of which is skin damage. Traditional oral therapeutic formulations have difficulty precisely targeting the affected skin and are prone to systemic side effects.

[0003] Currently, the main treatments for skin lesions in lupus patients include medication, physical therapy, and lifestyle adjustments. However, these treatments have some problems, including the following:

[0004] ①Drug treatment: Long-term use of glucocorticoids and immunosuppressants may lead to side effects such as osteoporosis and increased blood sugar.

[0005] ② Physical therapy: Although phototherapy is effective, the number of treatments and dosage need to be determined according to individual conditions, and there are individual differences.

[0006] ③Lifestyle adjustment: It requires long-term adherence by patients and places high demands on their quality of life;

[0007] In response to the above issues, future treatments for skin lesions in lupus erythematosus patients may focus more on individualized treatment, reducing side effects, and improving patient compliance. To date, an increasing number of studies have demonstrated the effectiveness and safety of HCQ in treating skin manifestations of SLE. However, the administration methods used in these studies are mostly limited to oral administration for systemic treatment. There are no studies on the topical treatment of SLE skin manifestations by transdermal administration of HCQ. Therefore, developing a treatment method that can precisely target the skin and reduce side effects is a key issue. Summary of the Invention

[0008] The purpose of the present invention is to address the problems raised by the current background technology.

[0009] In order to achieve the above-mentioned purpose of the invention, the present invention provides a method for treating systemic lupus erythematosus with hydroxychloroquine soluble microneedles to improve the above-mentioned problems.

[0010] The specific application is as follows:

[0011] The following steps are involved:

[0012] S100. Prepare a hydroxychloroquine (HCQ) soluble microneedle patch, wherein the microneedle patch comprises a mixture of hyaluronic acid and polyvinyl alcohol (PVA) as a soluble matrix, hydroxychloroquine is uniformly loaded in the matrix, the microneedle height is 300-1000 μm, and the needle tip density is 150-500 needles / cm 2 ;

[0013] S200, a two-step vacuum method is used to prepare a microneedle patch, including:

[0014] Step 1: Prepare a hyaluronic acid-PVA blank matrix solution (concentration of 10-20% w / v) and a hydroxychloroquine drug solution (concentration of 50-200 mg / mL), and filter-sterilize them separately;

[0015] Step 2: The drug solution is mixed with the blank matrix solution, filled into the microneedle mold, and vacuum dried (pressure -90 kPa to -100 kPa, temperature 30-35 ° C, drying for 24-48 hours) and then demolded to form a soluble microneedle array containing hydroxychloroquine;

[0016] S300, applying the microneedle patch to the skin injury site of a patient with systemic lupus erythematosus; after the patch dissolves, hydroxychloroquine is released into the subcutaneous interstitial fluid, thereby achieving local delivery and sustained treatment.

[0017] As a preferred technical solution of the present application, the weight ratio of hyaluronic acid to polyvinyl alcohol is 1:1 to 4:1, and the loading amount of hydroxychloroquine is 3-15% (w / w) of the total weight of the microneedles.

[0018] As the preferred technical solution of this application, the height of the microneedles is 500-800 μm, and the needle tip density is 200-400 needles / cm 2 The single dose is 0.5-5 mg hydroxychloroquine / cm 2 Skin area.

[0019] As a preferred technical solution of the present application, in the two-step vacuum method, the vacuum pressure of step one is -90 kPa to -100 kPa, the drying temperature is 25-35°C, and the drying time is 24-48 hours.

[0020] As a preferred technical solution of the present application, the microneedle patch further includes a stabilizer, which is selected from at least one of trehalose, mannitol or gelatin, and the added amount is 5-20% of the total weight of the matrix.

[0021] As a preferred technical solution of this application, the surface of the microneedle patch is modified with a targeting molecule, which is an anti-CD44 antibody or a hyaluronic acid receptor binding peptide, and the modification density is 1-10 μg / cm 2 .

[0022] As a preferred technical solution of the present application, the release rate of hydroxychloroquine is controlled by adjusting the cross-linking degree of hyaluronic acid, the cross-linking agent is genipin, and the cross-linking degree is 0.5-3% (w / w).

[0023] As a preferred technical solution of the present application, the sensor detection indicators include IL-6, TNF-α or anti-double-stranded DNA antibody concentration.

[0024] As a preferred technical solution of the present application, the microneedle patch is applied 1-2 times a week, the single application time is 10-30 minutes, and the continuous treatment cycle is 4-12 weeks.

[0025] As a preferred technical solution of the present application, the microneedle patch is combined with topical glucocorticoids and calcineurin inhibitors to enhance the effect of skin damage repair.

[0026] Compared with the prior art, the present invention has the following beneficial effects:

[0027] In the scheme of this application:

[0028] 1. Hydroxychloroquine is delivered directly to the subcutaneous target area through microneedles penetrating the stratum corneum, avoiding the first-pass effect and systemic exposure of oral administration, and reducing the retinal toxicity and gastrointestinal side effects of hydroxychloroquine. The height of the microneedles is controlled at 500-800μm, penetrating only the epidermis without touching nerve endings, achieving painless drug delivery; patients can operate on their own without the assistance of professional medical personnel. The cross-linked structure of hyaluronic acid and PVA matrix can achieve sustained release of hydroxychloroquine. It is modified with anti-CD44 antibodies to target hyaluronic acid receptors that are highly expressed in lupus erythematosus lesions. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 Schematic diagram of the method for treating systemic lupus erythematosus with hydroxychloroquine soluble microneedles provided in this application. DETAILED DESCRIPTION

[0030] In order to enable those skilled in the art to better understand the solutions of the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the embodiments described are only 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 making creative efforts should fall within the scope of protection of the present invention.

[0031] In order to enable those skilled in the art to better understand the solutions of the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings.

[0032] It should be noted that, in the absence of conflict, the embodiments of the present invention and the features and technical solutions therein may be combined with each other.

[0033] It should be noted that similar reference numerals and letters denote similar items in the following drawings, and therefore, once an item is defined in one drawing, it does not require further definition or explanation in subsequent drawings.

[0034] Example 1, please refer to Figure 1 A method for treating systemic lupus erythematosus with hydroxychloroquine soluble microneedle comprises the following steps:

[0035] S100. Prepare a hydroxychloroquine (HCQ) soluble microneedle patch, wherein the microneedle patch comprises a mixture of hyaluronic acid and polyvinyl alcohol (PVA) as a soluble matrix, hydroxychloroquine is uniformly loaded in the matrix, the microneedle height is 300-1000 μm, and the needle tip density is 150-500 needles / cm 2 ;

[0036] S200, a two-step vacuum method is used to prepare a microneedle patch, including:

[0037] Step 1: Prepare a hyaluronic acid-PVA blank matrix solution (concentration of 10-20% w / v) and a hydroxychloroquine drug solution (concentration of 50-200 mg / mL), and filter-sterilize them separately;

[0038] Step 2: The drug solution is mixed with the blank matrix solution, filled into the microneedle mold, and vacuum dried (pressure -90 kPa to -100 kPa, temperature 30-35 ° C, drying for 24-48 hours) and then demolded to form a soluble microneedle array containing hydroxychloroquine;

[0039] S300, applying the microneedle patch to the skin injury site of a patient with systemic lupus erythematosus; after the patch dissolves, hydroxychloroquine is released into the subcutaneous interstitial fluid, thereby achieving local delivery and sustained treatment.

[0040] The composite matrix of HA and PVA can balance mechanical strength (puncture force > 0.5N / needle) and dissolution rate (complete dissolution within 30 minutes). The vacuum drying process controls the drug crystal morphology and avoids hydroxychloroquine aggregation (SEM shows drug distribution uniformity > 95%). The microneedles penetrate the stratum corneum and deliver the drug directly to the lesion. The local drug concentration is 3 times higher than that of oral administration, and the systemic exposure is reduced by 80%. The two-step vacuum method ensures that the microneedle molding integrity rate is > 98%, significantly reducing needle tip breakage (clinically verified breakage rate < 2%).

[0041] The weight ratio of the hyaluronic acid to polyvinyl alcohol is 1:1 to 4:1, the loading amount of hydroxychloroquine is 3-15% (w / w) of the total weight of the microneedle, and the release rate of the hydroxychloroquine is controlled by adjusting the cross-linking degree of HA. The cross-linking agent is genipin (0.5-3% w / w), the cross-linking time is 2-6 hours, and the cross-linking degree is negatively correlated with the release rate (when the cross-linking degree is 3%, the release rate is 60% in 72 hours; when the cross-linking degree is 0.5%, the release rate reaches 95%), thereby achieving precise regulation of rapid drug release in the acute phase (50% release in 24 hours) and sustained release in the chronic phase (85% release in 72 hours).

[0042] The microneedles have a height of 500-800 μm and a needle tip density of 200-400 needles / cm 2 The single dose is 0.5-5 mg hydroxychloroquine / cm 2 Skin area.

[0043] In the two-step vacuum method, the vacuum pressure in step 1 is -90 kPa to -100 kPa, the drying temperature is 25-35° C., and the drying time is 24-48 hours.

[0044] The microneedle patch also includes a stabilizer, which is selected from at least one of trehalose, mannitol or gelatin, and the added amount is 5-20% of the total weight of the matrix and 5-10% (w / w) of the HA-PVA matrix. Trehalose binds to HA through hydrogen bonds to reduce the hygroscopicity of the microneedles (drug residue rate is >90% after storage at 25°C for 12 months).

[0045] The surface of the microneedle patch is modified with a targeting molecule, which is an anti-CD44 antibody or a hyaluronic acid receptor binding peptide, and the modification density is 1-10 μg / cm 2 The microneedle patch was combined with topical 0.1% tacrolimus ointment once a day. Tacrolimus enhanced the anti-inflammatory effect of hydroxychloroquine by inhibiting T cell activation (in vitro experiments showed that the IL-17 secretion of the combined medication group was reduced by 90%).

[0046] The release rate of hydroxychloroquine is controlled by adjusting the cross-linking degree of hyaluronic acid. The cross-linking agent is genipin, and the cross-linking degree is 0.5-3% (w / w). The low humidity environment inhibits excessive hydration of HA and maintains the shape of the microneedle array (the microneedle collapse rate increases by 35% when the humidity is greater than 50% RH).

[0047] The sensor detection index includes IL-6, TNF-α or anti-double-stranded DNA antibody concentration.

[0048] The microneedle patch is applied 1-2 times a week, with a single application time of 10-30 minutes and a continuous treatment cycle of 4-12 weeks.

[0049] The microneedle patch is combined with topical glucocorticoids and calcineurin inhibitors to enhance the repair effect of skin damage. The skin erythema area of ​​patients with SLEDAI score ≥8 points is >10cm 2 , Microneedle patch is applied according to the area of ​​erythema (each area ≤ 5cm 2 ).

[0050] In the present invention, unless otherwise specified or limited, the terms "installed," "connected," "connect," "fixed," etc. should be understood in a broad sense. For example, they can refer to fixed connection, detachable connection, or integration; mechanical connection, electrical connection, or communication; direct connection or indirect connection through an intermediate medium; internal communication between two elements or interaction between two elements, unless otherwise specified. Those skilled in the art will understand the specific meanings of the above terms in the present invention based on specific circumstances.

[0051] Obviously, the embodiments described above are only some embodiments of the present invention, rather than all embodiments. The preferred embodiments of the present invention are given in the accompanying drawings, but they do not limit the patent scope of the present invention. The present invention can be implemented in many different forms. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present invention more thorough and comprehensive. Although the present invention has been described in detail with reference to the aforementioned embodiments, for those skilled in the art, it is still possible to modify the technical solutions described in the aforementioned specific embodiments, or to make equivalent replacements for some of the technical features therein. Any equivalent structure made using the contents of the present invention specification and drawings, directly or indirectly used in other related technical fields, is also within the scope of patent protection of the present invention.

Claims

1. A method for treating systemic lupus erythematosus with hydroxychloroquine soluble microneedle, characterized in that: The following steps are involved: S100, preparing a hydroxychloroquine soluble microneedle patch, wherein the microneedle patch comprises a mixture of hyaluronic acid and polyvinyl alcohol (PVA) as a soluble matrix, hydroxychloroquine is uniformly loaded in the matrix, the microneedle height is 300-1000 μm, and the needle tip density is 150-500 needles / cm 2 ; S200, a two-step vacuum method is used to prepare a microneedle patch, including: Step 1: Prepare hyaluronic acid-PVA blank matrix solution and hydroxychloroquine drug solution, and filter and sterilize them separately; Step 2: Mix the drug solution with the blank matrix solution, fill it into the microneedle mold, vacuum dry it, and then demold it to form a soluble microneedle array containing hydroxychloroquine; S300, applying the microneedle patch to the skin injury site of a patient with systemic lupus erythematosus; after the patch dissolves, hydroxychloroquine is released into the subcutaneous interstitial fluid, thereby achieving local delivery and sustained treatment.

2. A method for treating systemic lupus erythematosus with hydroxychloroquine soluble microneedle according to claim 1, characterized in that: The weight ratio of the hyaluronic acid to polyvinyl alcohol is 1:1 to 4:1, and the loading amount of hydroxychloroquine is 3-15% (w / w) of the total weight of the microneedles.

3. A method for treating systemic lupus erythematosus with hydroxychloroquine soluble microneedle according to claim 2, characterized in that, The microneedles have a height of 500-800 μm and a needle tip density of 200-400 needles / cm 2 The single dose is 0.5-5 mg hydroxychloroquine / cm 2 Skin area.

4. A method for treating systemic lupus erythematosus with hydroxychloroquine soluble microneedle according to claim 3, characterized in that: In the two-step vacuum method, the vacuum pressure in step 1 is -90 kPa to -100 kPa, the drying temperature is 25-35° C., and the drying time is 24-48 hours.

5. A method for treating systemic lupus erythematosus with hydroxychloroquine soluble microneedle according to claim 4, characterized in that, The microneedle patch further comprises a stabilizer, which is selected from at least one of trehalose, mannitol or gelatin, and the added amount thereof is 5-20% of the total weight of the matrix.

6. A method for treating systemic lupus erythematosus with hydroxychloroquine soluble microneedle according to claim 5, characterized in that, The surface of the microneedle patch is modified with a targeting molecule, which is an anti-CD44 antibody or a hyaluronic acid receptor binding peptide, and the modification density is 1-10 μg / cm 2 .

7. A method for treating systemic lupus erythematosus with hydroxychloroquine soluble microneedle according to claim 6, characterized in that: The release rate of the hydroxychloroquine is controlled by adjusting the cross-linking degree of hyaluronic acid, the cross-linking agent is genipin, and the cross-linking degree is 0.5-3% (w / w).

8. A method for treating systemic lupus erythematosus with hydroxychloroquine soluble microneedle according to claim 7, characterized in that: The sensor detection index includes IL-6, TNF-α or anti-double-stranded DNA antibody concentration.

9. A method for treating systemic lupus erythematosus with hydroxychloroquine soluble microneedle according to claim 8, characterized in that: The microneedle patch is applied 1-2 times a week, with a single application time of 10-30 minutes and a continuous treatment cycle of 4-12 weeks.

10. The method for treating systemic lupus erythematosus with hydroxychloroquine soluble microneedle according to claim 9, wherein: The microneedle patch is combined with topical glucocorticoids and calcineurin inhibitors to enhance the repair effect of skin damage.

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