Abaparatide solution, application thereof, sectional type soluble microneedle and preparation method of sectional type soluble microneedle

Abstract

The invention discloses an abparatide solution and application thereof, a sectional type soluble microneedle and a preparation method, and belongs to the technical field of microneedle preparation, and the abparatide solution comprises the following components: 20.00-45.00 wt% of abparatide, 0.02-20.00 wt% of PVP (Polyvinyl Pyrrolidone) and water for injection. The application is an application of an abparatide solution in preparation of a sectional type soluble microneedle. According to the sectional type soluble microneedle, a medicine carrying section contains an abapalotide solution. By adding PVP, the sedimentation performance of a high-concentration abparatide solution is improved, residues of the abparatide solution on a needle body and a needle cavity base are avoided, a medicine carrying section is concentrated on a microneedle tip part, the medicine carrying section and a framework section are obviously layered, an abparatide medicine can be packaged on the needle tip part in a segmented manner, the carrying capacity of the medicine on the needle tip part is improved, and the medicine carrying capacity of the needle tip part is improved. And precise administration is realized.

Description

Technical Field

[0001] The present invention belongs to the technical field of microneedle preparation, and specifically relates to an abaloparatide solution that is easy to sediment, its application, segmented soluble microneedles, and a preparation method. Background Art

[0002] The existing abaloparatide soluble microneedles are in the form of a uniform one-piece microneedle made of a drug composition mixture, and the abaloparatide drug is evenly distributed throughout the microneedle. Under the application of an external force, when the microneedle is inserted into the skin and meets tissue fluid, the microneedle dissolves, thereby actively delivering the drug into the dermis. However, due to the large difference in skin thickness among different individuals (different skin sites), and depending on the force applied for each microneedle drug delivery, it is impossible to ensure that all microneedles can be completely inserted into the skin, and the depth of the microneedles inserted into the skin is not completely consistent, resulting in the total amount of drug actually entering the skin being less than the drug loading capacity of the microneedle to varying degrees, and it is impossible to achieve the precise solution amount of abaloparatide in the microneedle patch in the human body, and thus it is impossible to achieve the effect of quantitative drug delivery.

[0003] To achieve precise drug delivery, a solution containing abaloparatide needs to be segmented and provided at the tip of the microneedle. On the premise that the depth of the microneedle inserted into the skin is greater than half of the length of the microneedle body, regardless of whether the microneedle is completely inserted into the skin or the insertion depths are different, the drug-loaded tip part of the microneedle can dissolve in the skin, so that the abaloparatide drug is completely released, and thus precise control of drug delivery to the microneedle patch can be achieved.

[0004] When preparing the microneedle in layers for the existing abaloparatide microneedle solution, it is necessary to sequentially fill a section of abaloparatide solution and a section of base solution and perform a drying process. During the drying process, the abaloparatide microneedle drug at the tip diffuses towards the microneedle body and the base, resulting in no obvious boundary line in the tip part containing the abaloparatide drug, and it is impossible to achieve the segmented encapsulation of the drug at the tip, affecting precise drug delivery. And to make the drug loading amount of the abaloparatide solution in a section distributed only at 1 / 3 of the tip equal to or higher than the drug loading amount of the one-piece microneedle, it is necessary to increase the proportion of abaloparatide in the segmented solution of a section, about 20%-45%. However, it is found in actual production that a high-concentration abaloparatide solution has the problem of being not easy to sediment, and it cannot completely sediment and fill into the tip. Most of the abaloparatide solution remains at the needle body and the needle cavity base, resulting in limited drug loading amount at the tip part. Summary of the Invention

[0005] To solve the above technical problems, the present invention provides an abaloparatide solution that is easy to sediment, its application, segmented soluble microneedles, and a preparation method. The abaloparatide solution of the present invention improves the sedimentation performance of the high-concentration abaloparatide solution by adding PVP, avoids the residue of the abaloparatide solution at the needle body and the needle cavity base, and increases the drug loading amount at the tip part.

[0006] To achieve the above object, the present invention adopts the following technical solutions:

[0007] In a first aspect, the present invention provides a method for improving the sedimentation property of an abaloparatide solution, comprising the following:

[0008] Adjust the content of the abaloparatide to 20.00% to 45.00% by weight;

[0009] Adjust the content of PVP to 0.02% to 20.00% by weight.

[0010] The viscosity of the abaloparatide solution in the present invention is 20 - 100 mPa·s.

[0011] In certain embodiments, the average molecular weight of the PVP is 3,000 - 1,500,000 Da.

[0012] Preferably, the content of the PVP has the following relationship with the average molecular weight of the PVP:

[0013] When the average molecular weight of the PVP is 3,000 - 1,500,000 Da, adjust the content of the PVP to 5.00% to 20.00% by weight;

[0014] When the average molecular weight of the PVP is 10,000 - 20,000 Da, adjust the content of the PVP to 2.00% to 10.00% by weight;

[0015] When the average molecular weight of the PVP is 40,000 - 60,000 Da, adjust the content of the PVP to 0.5% to 5.00% by weight;

[0016] When the average molecular weight of the PVP is 300,000 - 400,000 Da, adjust the content of the PVP to 0.10% to 0.50% by weight;

[0017] Or when the average molecular weight of the PVP is 1,000,000 - 1,500,000 Da, adjust the content of the PVP to 0.02% to 0.20% by weight.

[0018] In a second aspect, the present invention provides an abaloparatide solution with easy sedimentation, containing the following components: 20.00% to 45.00% by weight of abaloparatide, 0.02% to 20.00% by weight of PVP, and water for injection.

[0019] The viscosity of the abaloparatide solution in the present invention is 20 - 100 mPa·s.

[0020] In certain embodiments, the average molecular weight of the PVP is 3,000 - 1,500,000 Da.

[0021] Preferably, the abaloparatide solution has one of the following characteristics:

[0022] (a) When the average molecular weight of PVP is 3,000 - 8,000 Da, PVP is 5.00 wt% - 20.00 wt%;

[0023] (b) When the average molecular weight of PVP is 10,000 - 20,000 Da, PVP is 2.00 wt% - 10.00 wt%;

[0024] (c) When the average molecular weight of PVP is 40,000 - 60,000 Da, PVP is 0.5 wt% - 5.00 wt%;

[0025] (d) When the average molecular weight of PVP is 300,000 - 400,000 Da, PVP is 0.10 wt% - 0.50 wt%;

[0026] (e) When the average molecular weight of PVP is 1,000,000 - 1,500,000 Da, PVP is 0.02 wt% - 0.20 wt%.

[0027] Thirdly, the present invention provides the use of the abaloparatide solution in the preparation of segmented soluble microneedles.

[0028] Fourthly, the present invention provides a segmented soluble microneedle, comprising a drug-loading segment, and the drug-loading segment contains the abaloparatide solution.

[0029] The segmented soluble microneedle of the present invention can be two-segment or multi-segment.

[0030] Fifthly, the present invention provides a preparation method of the segmented soluble microneedle, comprising the following steps:

[0031] (1) Inject the abaloparatide solution into a microneedle mold to form a drug-loading segment, and let the microneedle mold with the drug-loading segment stand and be dried;

[0032] (2) Inject a soluble polymer solution into the microneedle mold after the drying treatment in step (1) to form a skeleton segment, dry, and demold to obtain the segmented soluble microneedle.

[0033] The standing conditions in step (1) of the present invention are: humidity 80% - 90%, temperature 20 - 30 °C, and the standing time is less than 1 hour; preferably, the standing time is 1 - 24 hours.

[0034] In step (1) of the present invention, the drying is to reduce the moisture in the drug-loading section to make the surface of the drug-loading section dry or completely dry. Preferably, the drying conditions are: drying for more than 2 hours in an environment with a humidity of 10%-60% and a temperature of 20-30°C; more preferably, the drying time is 2-48 hours.

[0035] In some embodiments, according to the specific form of the segmented soluble microneedles, such as two-segment or multi-segment, the soluble polymer solution can be injected into the microneedle mold dried in step (2) once, twice or multiple times, dried, and peeled off to obtain the segmented soluble microneedles.

[0036] The soluble polymer solution of the present invention is a solution of a soluble microneedle skeleton material without abaloparatide. Specifically, the soluble microneedle skeleton material is a conventional soluble microneedle skeleton material in the art, and those skilled in the art can select according to actual needs. For example, the soluble microneedle skeleton material can be selected from at least one of polyester, polyhydroxyalkanoate, copolymer of 3-hydroxybutyrate and 3-hydroxyvalerate, polyacrylamide, modified polypropylene, polyhydroxyalkanoate-polyethylene glycol, poly-α-hydroxy acid, poly-β-hydroxy acid, polyhydroxybutyrate, polyester amide, polycaprolactone, polylactide, polyglycolic acid, polydioxanone, polyorthoester, polyether ester, polyanhydride, glycolic acid-trimethylenecarbonate copolymer, polyphosphate, polyphosphate urethane, polyamino acid, polycyanoacrylate, polytrimethylene carbonate, polycarbonate, polyphosphocreatine, chitosan, dextran, heparin, hyaluronic acid, sucrose, trehalose, mannitol, chondroitin sulfate, Tween 80, gelatin, poly(lactic-co-glycolic acid), polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, trehalose, maltose, hydroxypropyl-β-cyclodextrin, polylactic acid, polyethylene glycol, glycerol, sodium chloride, inulin, starch, and glycogen.

[0037] The concentration of the soluble microneedle skeleton material in the soluble polymer solution of the present invention only needs to meet the conventional processing requirements in the art. The mass percentage ratio of the soluble microneedle skeleton material in the soluble polymer solution is less than 30%, preferably 30%-50%; more preferably 30%-45%.

[0038] In some specific embodiments, the segmented soluble microneedles are two-segment, and the preparation method includes the following steps:

[0039] S1. Inject the abaloparatide solution into the microneedle mold, and let it stand at a humidity of 80%-90% and a temperature of 20-30°C for at least 1 hour to form a drug-loading section of the abaloparatide solution, and completely settle and fill the tip part.

[0040] S2. Dry the micro-needle mold filled in step S1 for more than 2 hours in an environment with a humidity of 10%-60% and a temperature of 20-30°C to reduce the moisture content in the drug-loading section and make the surface of the drug-loading section dry or completely dry and solidify;

[0041] S3. Inject a soluble polymer solution into the micro-needle mold dried and solidified in step S2 to form a backbone section, and then dry and demold to obtain the segmented soluble micro-needles.

[0042] Preferably, the standing time in step S1 is 1-24 hours; the drying time in step S2 is 2-48 hours; the drying in step S3 is: drying at a humidity of 10%-90% and a temperature of 20-30°C for 15-72 hours.

[0043] Preferably, before the drying in S3, a semi-drying step is further included, specifically:

[0044] S3-1. Semi-dry the micro-needle mold filled with the soluble micro-needle solution in step S3 and fix the gasket;

[0045] S3-2. Dry the micro-needle mold with the gasket fixed in step S3-1, and peel the micro-needles and the gasket from the micro-needle mold to obtain the segmented soluble micro-needles.

[0046] More preferably, the conditions for the semi-drying in step S3-1 are: place for 3-60 minutes at a humidity of 30%-70% and a temperature not lower than 10°C, and then place for 2-5 minutes at a humidity of 40%-90% and a temperature of 20-45°C.

[0047] More preferably, the drying in step S3-2 is: drying at a humidity of 10%-90% and a temperature of 20-30°C for 15-72 hours.

[0048] In some specific embodiments, the preparation method of the segmented soluble micro-needles includes the following steps:

[0049] S1. Inject an abaloparatide solution into the micro-needle mold, and stand at a humidity of 80%-90% and a temperature of 20-30°C for not less than 1 hour to form a drug-loading section with the abaloparatide solution, and completely settle and fill it into the tip part;

[0050] S2. Dry the micro-needle mold filled in step S1 for more than 2 hours in an environment with a humidity of 10%-60% and a temperature of 20-30°C to reduce the moisture content in the drug-loading section and make the surface of the drug-loading section dry or completely dry and solidify;

[0051] S3. Inject a soluble polymer solution into the micro-needle mold dried and solidified in step S2 to form a backbone section;

[0052] S4. Place the microneedle mold filled with the soluble polymer solution in step S3 at a humidity of 30%-70% and a temperature of not less than 10°C for 3-60 minutes, and then place it at a humidity of 40%-90% and a temperature of 20-45°C for 2-5 minutes for semi-drying, and fix the gasket.

[0053] S5. Dry the microneedle mold with the gasket fixed in step S4 at a humidity of 10%-90% and a temperature of 20-30°C for 15-72 hours. The microneedles adhere to the gasket at the same time. Use tools to separate the microneedles and the gasket from the mold to obtain segmented soluble microneedles.

[0054] Preferably, the standing time in step S1 is 1-24 hours; the drying time in step S2 is 2-48 hours.

[0055] The "injection" described in the present invention is a conventional perfusion method into the microneedle mold in the art, including but not limited to high-pressure spraying, centrifugation, vacuum adsorption or self-leveling.

[0056] The beneficial effects of the present invention are as follows:

[0057] (1) By adding PVP, the solution of abaloparatide in the present invention improves the sedimentation performance of the high-concentration abaloparatide solution, avoids the residue of the abaloparatide solution at the needle body and the needle cavity base, and the drug-loading section is concentrated in the 1 / 3-1 / 2 part of the microneedle tip, improving the drug loading capacity at the tip part.

[0058] (2) The segmented soluble microneedles prepared in the present invention effectively solve the problem of the diffusion of abaloparatide in the drug-loading section into the skeleton section. The drug-loading section and the skeleton section are clearly stratified, and the abaloparatide drug can be segmented and encapsulated at the needle tip part, realizing precise drug delivery. Description of the Drawings

[0059] Figure 1 The segmented soluble microneedles prepared in Examples 1-10.

[0060] Figure 2 The segmented soluble microneedles prepared in Comparative Example 1.

[0061] Figure 3 The segmented soluble microneedles prepared in Comparative Example 3.

[0062] Figure 4 The segmented soluble microneedles prepared in Comparative Example 4.

[0063] Figure 5 The segmented soluble microneedles prepared in Comparative Example 5.

[0064] Figure 6 The segmented soluble microneedles prepared in Comparative Example 6.

[0065] Figure 7 The segmented soluble microneedles prepared in Comparative Example 2.

[0066] Figure 8 The segmented soluble microneedles prepared in Comparative Example 7.

[0067] Figure 9 One of the segmented soluble microneedles prepared in Comparative Example 8.

[0068] Figure 10 Another one of the segmented soluble microneedles prepared in Comparative Example 8. Detailed implementation manners

[0069] The following specific examples illustrate the implementation manners of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. The present invention can also be implemented or applied through other different specific implementation manners. Various details in this specification can also be modified or changed based on different viewpoints and applications without departing from the spirit of the present invention.

[0070] Before further describing the specific implementation manners of the present invention, it should be understood that the protection scope of the present invention is not limited to the specific implementation manners described below; it should also be understood that the terms used in the embodiments of the present invention are for describing specific implementation manners, rather than for limiting the protection scope of the present invention.

[0071] When the embodiments give a numerical range, it should be understood that unless otherwise specified in the present invention, both endpoints of each numerical range and any value between the two endpoints can be selected. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the technical field to which the present invention belongs.

[0072] The present invention does not limit the sources of the raw materials used. Unless otherwise specified, the raw materials used in the present invention are all common commercially available products in this technical field.

[0073] Test method for viscosity

[0074] 1. Start the Thermo Scientific HAAKE Viscotester iQ rheometer, connect the rotor to the device, turn on the computer and start the viscosity test software.

[0075] 2. Use a pipette and a viscous pipette tip to take 0.5 mL of the solution and drop it onto the center of the detection platform.

[0076] 3. Lower the rotor to the bottom of the detection platform with the dropped solution, and confirm that the solution can cover the circumference of the rotor.

[0077] 4. The viscosity test software system automatically identifies the rotor and performs the viscosity test of the solution.

[0078] 5. Read and record the viscosity test results.

[0079] [Examples and Comparative Examples]

[0080] Prepare the segmented soluble microneedles described in Table 1 and Table 2 according to the following preparation method.

[0081] Preparation method:

[0082] S1. Inject the abaloparatide solution into the microneedle mold, and let it stand for no less than 1 hour at a humidity of 80%-90% and a temperature of 25°C to form a drug-loaded segment of the abaloparatide solution, and completely settle and fill it into the tip part;

[0083] S2. Dry the microneedle mold filled in step S1 for 15 hours in an environment with a humidity of 50% and a temperature of 25°C to reduce the moisture in the drug-loaded segment and make the surface of the drug-loaded segment dry or completely dry and solidify;

[0084] S3. Inject the soluble polymer solution into the microneedle mold dried and solidified in step S2 to form a skeleton segment, and let it stand for 7 h at a humidity of 90% and a temperature of 23°C to completely settle the skeleton segment into the needle cavity;

[0085] S4. Place the microneedle mold filled with the soluble polymer solution in step S3 at a humidity of 50% and a temperature of 15°C for 10 min, and then place it at a humidity of 80% and a temperature of 30°C for 2 min for semi-drying, and fix the gasket;

[0086] S5. Dry the microneedle mold with the gasket fixed in step S4 at a humidity of 50% and 23°C for 20-24 h. The microneedles adhere to the gasket at the same time. Use tools to separate the microneedles and the gasket from the mold to obtain the segmented soluble microneedles.

[0087] Segmented soluble microneedles prepared in Examples 1-10 of Table 1

[0088]

[0089]

[0090] Segmented soluble microneedles prepared in Comparative Examples 1-8 of Table 2

[0091]

[0092] Among them,

[0093] Abaloparatide, CAS No.: 247062-33-5;

[0094] Glutathione, CAS No.: 70-18-8;

[0095] Chondroitin sulfate, CAS No.: 9007-28-7;

[0096] Trehalose, CAS No.: 6138-23-4;

[0097] Mannitol, CAS No.: 87-78-5;

[0098] Dextran, CAS No.: 9004-54-0;

[0099] Sucrose, CAS No.: 57-50-1;

[0100] PVA, CAS No.: 9002-89-5.

[0101] PVP-a: The average molecular weight is 3,000 - 8,000 Da;

[0102] PVP-b: The average molecular weight is 10,000 - 20,000 Da;

[0103] PVP-c: The average molecular weight is 40,000 - 60,000 Da;

[0104] PVP-d: The average molecular weight is 300,000 - 400,000 Da;

[0105] PVP-e: The average molecular weight is 1,000,000 - 1,500,000 Da.

[0106] As can be seen from Table 1, for the segmented soluble microneedles prepared by the present invention using the abaloparatide solution, the drug-loading section is concentrated in the tip part of the microneedles, and there is basically no diffusion in the needle body and the base. The drug-loading section and the skeleton section are clearly stratified, and the drug encapsulation at the tip can be realized, and the drug loading amount of abaloparatide at the tip part can be increased, as Figure 1 shown.

[0107] Comparing Example 2 with Comparative Example 1, it can be seen that the high-concentration abaloparatide solution of a single component has poor sedimentation performance and cannot be completely precipitated and filled into the tip. Part of the solution remains in the needle cavity base and the needle body. After the formed drug-loading section and the skeleton section are fused, abaloparatide diffuses into the skeleton section, resulting in no obvious boundary between the drug-loading section and the skeleton section, and the drug encapsulation at the tip cannot be realized, and the drug loading amount of abaloparatide at the tip part is small, as Figure 2 shown.

[0108] Comparing Example 2 with Comparative Examples 3 - 6, it can be seen that adding conventional excipients such as chondroitin sulfate, trehalose, mannitol and PVA to the high-concentration abaloparatide solution cannot improve the sedimentation performance of the abaloparatide solution. There is a large amount of abaloparatide solution remaining in the needle body and the needle cavity base. The drug-loading section and the skeleton section of the prepared segmented soluble microneedles are not stratified, and the drug-loading section cannot aggregate at the tip part, asFigures 3 - 6 as shown

[0109] Comparing Example 2 with Comparative Example 2, it can be seen that when the drug carried is replaced by glutathione, there is no delamination between the drug-loading section and the skeleton section of the prepared segmented soluble microneedles, and the drug-loading section cannot aggregate at the tip part, as Figure 7 shown

[0110] Comparing Example 2 with Comparative Example 7 and Example 6 with Comparative Example 8, it can be seen that when the viscosity of the abaloparatide solution is not within the range of 20-100 mPa·s, there is no delamination between the drug-loading section and the skeleton section of the prepared segmented soluble microneedles, as Figures 8 - 9 shown; among them, due to the too high viscosity of the solution in the drug-loading section in Comparative Example 8 and poor fluidity, the drug-loading section cannot completely settle and aggregate at the tip part, resulting in a hollow structure at the tip. When the microneedles are separated from the mold, the needle tip section is prone to needle breakage, as Figure 10 shown

[0111] The above is a further description of the present invention in combination with specific embodiments, but these embodiments are merely exemplary and do not constitute any limitation to the scope of the present invention. Those skilled in the art should understand that the details and forms of the technical solutions of the present invention can be modified or replaced without departing from the spirit and scope of the present invention, but such modifications and replacements all fall within the protection scope of the present invention.

Claims

1. An abaloparatide solution prone to sedimentation, characterized in that, It contains the following components: apalutamide 20.00% - 45.00% by weight, PVP 0.02% - 20.00% by weight, and water for injection.

2. The abaloparatide solution according to claim 1, wherein The viscosity of the apalutamide solution is 20 - 100 mPa·s.

3. The abaloparatide solution according to claim 1, characterized in that, The average molecular weight of the PVP is 3,000 - 1,500,000 Da.

4. The abaloparatide solution according to claim 3, wherein, It contains one of the following characteristics: (a) When the average molecular weight of PVP is 3,000 - 8,000 Da, PVP is 5.00% - 20.00% by weight; (b) When the average molecular weight of PVP is 10,000 - 20,000 Da, PVP is 2.00% - 10.00% by weight; (c) When the average molecular weight of PVP is 40,000 - 60,000 Da, PVP is 0.5% - 5.00% by weight; (d) When the average molecular weight of PVP is 300,000 - 400,000 Da, PVP is 0.10% - 0.50% by weight; (e) When the average molecular weight of PVP is 1,000,000 - 1,500,000 Da, PVP is 0.02% - 0.20% by weight.

5. Use of the apalutamide solution according to any one of claims 1 - 4 in the preparation of segmented soluble microneedles.

6. A segmented soluble microneedle, characterized in that, It includes a drug - loaded segment, and the drug - loaded segment contains the apalutamide solution according to any one of claims 1 - 4.

7. The preparation method of the segmented soluble microneedles according to claim 6, characterized in that, It includes the following steps: (1) Inject the apalutamide solution according to any one of claims 1 - 4 into a microneedle mold to form a drug - loaded segment, and let the microneedle mold with the drug - loaded segment stand and be dried; (2) Inject a soluble polymer solution into the microneedle mold after the drying treatment in step (1) to form a skeleton segment, dry, and demold to obtain segmented soluble microneedles.

8. The preparation method according to claim 7, characterized in that, The conditions for standing in step (1) are: humidity 80% - 90%, temperature 20 - 30°C, and the standing time is not less than 1 hour; preferably, the standing time is 1 - 24 hours.

9. The preparation method according to claim 7, characterized in that, The conditions for the drying treatment in step (1) are: drying in an environment with humidity 10% - 60% and temperature 20 - 30°C for more than 2 hours; preferably, the drying time is 2 - 48 hours.

10. A method for improving the sedimentation property of abaloparatide solution, characterized in that, It contains the following: Adjust the content of apalutamide to 20.00% - 45.00% by weight; Adjust the content of PVP to 0.02% - 20.00% by weight.

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