WO2023143358A1 - Pharmaceutical composition, microneedle formulation, microneedle drug delivery system, preparation method and use - Google Patents

Abstract

The present application relates to a pharmaceutical composition, a microneedle formulation, a microneedle drug delivery system, a preparation method and use. The pharmaceutical composition comprises the following components in parts by weight: 0.01-18 parts of a first active ingredient, 0-5 parts of a penetration-promoting ingredient, 1-50 parts of a polymer base material ingredient, 0-5 parts of a first functional ingredient, 40-90 parts of an aqueous solvent, and 0-5 parts of an organic solvent. The first active ingredient is a drug for preventing and/or treating osteoporosis, and the first functional ingredient is a protective agent and/or a dissolution promoter.

Description

Pharmaceutical composition, microneedle preparation, microneedle drug delivery system, preparation method and application

related application

This application requires a Chinese patent application filed on January 28, 2022, with application number CN2022101088283, titled "Pharmaceutical composition, medicinal microneedle, microneedle preparation, drug delivery system, preparation method and application", filed in 2023 The priority of the Chinese patent application with the application number CN2023100253714 and titled "Pharmaceutical composition, microneedle preparation, microneedle drug delivery system, preparation method and application" filed on January 9, 2020, the aforementioned two Chinese The entirety of the patent application is incorporated by reference.

technical field

This application relates to the technical field of pharmaceutical preparations and drugs for treating osteoporosis, in particular to pharmaceutical compositions, microneedle preparations, microneedle drug delivery systems, preparation methods and applications, and further to pharmaceutical compositions, medicinal microneedles, microneedle Preparation, drug delivery system, preparation method and application in preventing and/or treating osteoporosis or related bone diseases.

Background technique

Osteoporosis (osteoporosis) is a systemic bone disease in which bone density and bone quality decrease due to various reasons, bone microstructure is destroyed, bone fragility increases, and fractures are prone to occur. Prevention and treatment strategies for osteoporosis include basic measures and drug therapy. Among the basic measures, including strengthening diet, paying attention to exercise, avoiding bad living habits, preventing falls, etc., another important item is to take basic supplements, namely calcium and vitamin D.

The most common of these treatments is the oral or intravenous administration of bisphosphonates. However, an undesirable side effect of bisphosphonate administration is decreased bone formation (MacLean 2008). Anabolic agents provide an alternative to antiresorptive agents. The current administration method for treating osteoporosis is subcutaneous injection, but there are problems such as poor compliance, inability to self-administer, pain in the route of administration, and strong irritation. The new technology of soluble microneedles is a new type of drug delivery method. The microneedle array penetrates into the skin and opens the channel of the skin. The active ingredient enters the human body directly from the channel to play a role, avoiding the problems of poor compliance of patients caused by injection and not inconvenient. Affects the absorption route of drugs. However, when using microneedle preparations to deliver drugs related to osteoporosis treatment, it is necessary to provide sufficient puncture efficiency and appropriate solubility and other preparation properties to achieve better pharmacokinetics and drug delivery. .

Based on this, it is necessary to further develop pharmaceutical preparations that can be used for the prevention and/or treatment of osteoporosis.

Contents of the invention

Based on this, the purpose of this application includes providing a pharmaceutical composition that can be used to prevent and/or treat osteoporosis or related bone disorders, the pharmaceutical composition contains The active ingredient of the disease can be made into medicinal microneedles, pharmaceutical preparations (such as microneedle preparations), microneedle drug delivery systems, etc.

In the first aspect of the present application, a pharmaceutical composition is provided, which may include the following components in parts by weight:

in,

The first active ingredient is a drug for preventing and/or treating osteoporosis or related bone disorders;

The first functional ingredient is a protective agent and/or a dissolution accelerator (i.e., the first functional ingredient is a protective agent, a dissolution accelerator, or a combination thereof);

The organic solvent is a pharmaceutically acceptable organic solvent.

In some embodiments, the total parts by weight of the pharmaceutical composition is 100 parts;

Optionally, based on 100 parts by weight of the pharmaceutical composition, the parts by weight of the first active ingredient are 0.01-15 parts by weight, and the parts by weight of the aqueous solvent are 50-90 parts by weight.

In some embodiments, based on any of the foregoing embodiments, the pharmaceutical composition may further include the following components:
0-5 parts of solubilizer;
Bacteriostatic agent 0-1 part; and suspending agent 0-10 part;

Wherein, the weight part of at least one of the solubilizer, the bacteriostat and the suspending agent is not zero.

In some embodiments, based on any one of the foregoing embodiments, the pharmaceutical composition further includes a pH regulator.

In some embodiments, based on any of the foregoing embodiments, the first active ingredient is selected from one or more of the following group: bone resorption inhibitors, bone formation agents, bone morphogenetic protein 9, activin A , semaphorin 3A, calcium, vitamin D, strontium, estrogen drugs, selective estrogen receptor modulators, pharmaceutically acceptable salts of any of the foregoing, isofunctional derivatives of any of the foregoing, and Any one of the isomorphs, and any one of the aforementioned markers. In some embodiments, based on any of the foregoing embodiments, the pharmaceutical composition satisfies any one or more of the following characteristics:

The dry weight ratio of the first active ingredient in the pharmaceutical composition is 0.1% to 30%; further, it can be any of the following ranges: 1% to 30%, 5% to 30%, 10% %～30%, 10%～15%, 15%～25% and 25%～30%;

The penetration-promoting component is selected from one or more of the following groups: surfactants, dimethyl sulfoxide and its analogues, azone compounds, pyrrolone derivatives, alcohol compounds, fatty acid compounds and penetration-promoting peptide;

The macromolecular substrate component is one or more of polyglycolic acid, polyvinylpyrrolidone, macromolecular sugar and macromolecular sugar derivatives; the weight average molecular weight of the macromolecular sugar and macromolecular sugar derivatives is independent Earth greater than 1000Da;

The molecular weight of the polymer substrate component is 0.5 to 2 million Daltons;

The first functional component is selected from one or more of low molecular weight alcohol compounds, low molecular weight carbohydrate compounds and heparin; wherein, the low molecular weight alcohol compound is mannitol; the low molecular weight carbohydrate compounds include Glucose, fructose, a-D-mannopyranose, mannose, inosose, sucrose, lactose, trehalose, maltose, dextran, raffinose, inulin, dextran, maltodextrin, soluble starch sugar, maltopolysaccharide, cyclic Dextrin, sucrose octasulfate, and derivatives of any of the foregoing; the weight-average molecular weights of the low-molecular-weight alcohol compounds and low-molecular-weight sugar compounds are each independently less than 5000Da;

The aqueous solvent is selected from water or an aqueous solution of a pH buffer; the pH of the aqueous solution of the pH buffer is 4 to 9; the pH buffer is selected from sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate , one or more of dipotassium hydrogen phosphate, hydrochloric acid and sodium hydroxide;

The organic solvent contains one or more of propylene glycol, dimethyl sulfoxide and ethanol.

In some embodiments, based on any of the foregoing embodiments, the polymer substrate component is a combination of polyvinylpyrrolidone and macromolecule sugar or its derivatives;

Optionally, in parts by weight, the pharmaceutical composition includes the following components: 0.1-18 parts of the first active ingredient, 5-40 parts of polyvinylpyrrolidone, and 0.5-25 parts of the macromolecule Sugar or its derivatives and 40 to 90 parts of the aqueous solvent;

Optionally, based on 100 parts by weight of the total pharmaceutical composition, the pharmaceutical composition is composed of the following components by weight: 0.1 to 18 parts of the first active ingredient, 5 to 18 parts by weight. 40 parts of the polyvinylpyrrolidone, 0.5-25 parts of the macromolecular sugar or its derivatives and 40-90 parts of the aqueous solvent;

Optionally, based on 100 parts by weight of the total pharmaceutical composition, the pharmaceutical composition is composed of the following components by weight: 0.1 to 18 parts of the first active ingredient, 5 to 18 parts by weight. 40 parts of the polyvinylpyrrolidone, 0.5-20 parts of the macromolecular sugar or its derivatives and 40-90 parts of the aqueous solvent;

Optionally, based on 100 parts by weight of the total pharmaceutical composition, the pharmaceutical composition is composed of the following components by weight: 0.1 to 15 parts of the first active ingredient, 5 to 15 parts by weight. 40 parts of the polyvinylpyrrolidone, 0.5-20 parts of the macromolecular sugar or its derivatives and 40-90 parts of the aqueous solvent;

Optionally, the sum of the parts by weight of the polyvinylpyrrolidone and the macromolecule sugar or its derivatives is 10-50 parts;

Optionally, the macromolecular sugar or its derivative is dextran or its derivative;

Optionally, the macromolecular sugar or its derivative is dextran;

Optionally, the first active ingredient is parathyroid hormone-related peptide, and further optionally, the first active ingredient is one or more of abaloparatide, teriparatide and abalatide kind;

Optionally, the weight average molecular weight of the polyvinylpyrrolidone is 3 to 1.5 million daltons; further optionally, the weight average molecular weight of the polyvinylpyrrolidone is 4 to 1.5 million daltons; further optionally , the weight average molecular weight of the polyvinylpyrrolidone is 250,000 to 1,500,000 Daltons;

Optionally, the weight-average molecular weight of the macromolecular sugar or its derivatives is 10-80 kDa; further optionally, the weight-average molecular weight of the macromolecular sugar or its derivatives is 20-70 kDa.

In some embodiments, based on any of the foregoing embodiments, the pharmaceutical composition satisfies any one or more of the following characteristics:

The solubilizer is selected from one or more of alcohol solubilizers, cyclodextrin solubilizers and second surfactants; wherein, the alcohol solubilizers include methanol, propylene glycol and small molecule polyethylene glycol ; The cyclodextrin solubilizer includes hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin; the second surfactant includes Tween 80 and polysorbate; the small Molecular weight average molecular weight of polyethylene glycol ≤ 1000Da;

The bacteriostatic agent is selected from one or more of quaternary ammonium salt bacteriostatic agents, alcohol bacteriostatic agents, ester bacteriostatic agents, acid bacteriostatic agents and phenolic bacteriostatic agents;

Described suspending agent is selected from at least one in low molecular weight suspending agent and macromolecule suspending agent; Wherein, described low molecular weight suspending agent comprises one or more in glycerol and syrup, and described low molecular weight suspending agent The weight-average molecular weight of the molecular weight suspending agent is less than or equal to 1000Da; The polymer suspending agent includes cellulose suspending agent, carbomer, povidone, dextran, sodium alginate, agar and starch slurry one or more of .

In the second aspect of the present application, there is provided a microneedle preparation comprising the pharmaceutical composition described in the first aspect of the present application.

In some embodiments, the microneedle preparation is a microneedle patch.

In some embodiments, the microneedle preparation (which may be a microneedle patch) includes a microneedle body and a base, and the microneedle body is a microprojection protruding from the base; the microneedle body For soluble microneedles, the substrate is soluble.

In the third aspect of the present application, there is provided a microneedle drug delivery system, including the microneedle preparation described in the second aspect of the present application, and also including a nano-drug delivery system connected to the medicinal microneedle or the microneedle preparation system.

In some embodiments, the nano drug delivery system is selected from one or more of vesicles, micelles, cells, liposomes, microcapsules, viruses and vaccines;

The nano drug delivery system carries components that have preventive and/or therapeutic effects on osteoporosis or related bone disorders; wherein the related bone disorders include osteopenia, osteoarthritis and fractures.

In a fourth aspect of the present application, a method for preparing a microneedle preparation is provided, comprising the following steps:

preparing a mixed solution comprising the pharmaceutical composition described in the first aspect of the present application;

Under negative pressure conditions, inject the mixed solution into a female mold with a microneedle forming cavity;

drying and demoulding to obtain the microneedle preparation.

In some embodiments, the mixed solution is prepared by a method comprising the following steps:

mixing the polymer substrate components with the aqueous solvent to form a blank solution;

Other ingredients in the pharmaceutical composition are mixed with the blank solution to form a drug-containing solution, that is, the mixture.

In some embodiments, the preparation method meets one or more of the following characteristics:

The mass concentration of the polymer substrate component in the blank solution is 5wt% to 50wt%;

The vacuum degree of the negative pressure condition is -0.05MPa to -0.1MPa;

The drying temperature is <30°C;

The drying time is 8h～24h.

In the fifth aspect of the present application, the application of the pharmaceutical composition described in the first aspect of the present application in the preparation of pharmaceutical preparations for preventing and/or treating osteoporosis or related bone diseases is provided.

In the fifth aspect of the present application, there is also provided the microneedle preparation described in the second aspect of the present application, or the microneedle drug delivery system described in the third aspect of the present application, or the preparation method described in the fourth aspect of the present application. The obtained microneedle preparation is used as a pharmaceutical preparation for preventing and/or treating osteoporosis or related bone diseases.

In some embodiments, the application satisfies any one or more of the following characteristics:

Associated bone disorders include one or more of osteopenia, osteoarthritis, and fractures;

The pharmaceutical preparation for preventing and/or treating osteoporosis or related bone disorders is a transdermal patch;

Said use comprises one or more of improving bone mineral density, improving trabecular bone score, and reducing fractures;

The pharmaceutical preparation for preventing and/or treating osteoporosis or related bone disorders is used for administration on the abdomen or thigh.

In the sixth aspect of the present application, there is provided a method for preventing and/or treating osteoporosis or related bone disorders, comprising administering the microneedle preparation described in the second aspect of the present application, or the method described in the third aspect of the present application A microneedle drug delivery system, or a microneedle preparation prepared by the preparation method described in the fourth aspect of the present application.

In some embodiments, the method satisfies any one or more of the following characteristics:

Associated bone disorders include one or more of osteopenia, osteoarthritis, and fractures;

The subject is a mammal;

The subject suffers from one or more of osteoporosis, osteopenia, osteoarthritis and fracture;

The mode of administration is transdermal administration;

Applying the microneedle formulation includes applying a force to the microneedle formulation sufficient to drive one or more of the microprojections through the stratum corneum of the subject;

The application site is on the abdomen or the arm or thigh area.

The pharmaceutical composition provided in this application contains active ingredients that can prevent and/or treat osteoporosis or related bone diseases, and can be made into medicinal microneedles, pharmaceutical preparations (such as microneedle preparations), and microneedle drug delivery systems etc., thereby being used for the prevention and/or treatment of osteoporosis or related bone disorders. Compared with the single administration method of traditional macromolecular pharmaceutical preparations (such as subcutaneous injection), the active ingredients in the pharmaceutical composition can be administered through the skin, which avoids the problems of poor patient compliance caused by injection and does not affect the drug. Advantages of absorption.

In some preferred schemes, the pharmaceutical composition provided by the application contains ingredients for the prevention and/or treatment of osteoporosis or related bone disorders Drugs (such as parathyroid hormone-related peptides, parathyroid hormone analogs, etc.), and can be made into microneedle preparations or microneedle drug delivery systems to achieve transdermal delivery of polypeptide drugs.

The medicinal microneedles prepared by the pharmaceutical composition in this application are soluble microneedles. Under the condition of external force, the microneedle can be inserted into the skin, and the drug can be actively delivered to the skin by dissolving in the interstitial fluid. The microneedle material can be degraded and eliminated in the skin. During the dissolving process of the soluble microneedle, all the drug in the microneedle is released, which can be controlled The drug loading of microneedles enables minimally invasive application and quantitative drug delivery; the dissolution of microneedles can also solve the secondary hazards of medical waste from needles after administration.

The substrate in the microneedle preparation provided by the present application can be soluble, and can be peeled off from the skin after administration and dissolution. The aforementioned "soluble" means that it can disintegrate after being inserted into the skin, thereby releasing active ingredients with therapeutic effects.

The microneedle preparation and microneedle drug delivery system provided by this application can solve some defects in the administration of traditional macromolecular drug preparations, such as the inability to achieve sustained release and the risk of toxicity due to high initial concentration.

Compared with transdermal injection, drug administration through the pharmaceutical microneedle, microneedle preparation or microneedle drug delivery system of the present application can improve the patient's drug compliance.

The microneedle preparation and microneedle drug delivery system provided by this application are convenient to use, easy to operate, have good permeability of active ingredients, high bioavailability of drugs, can realize precise drug delivery, and can solve patients with osteoporosis or related bone diseases Limitations of use (such as requiring a doctor's injection) and poor compliance.

Both the microneedle preparation and the microneedle drug delivery system provided in this application can be stored in a solid form, which is beneficial to the stability of the active ingredients contained therein, and does not require too strict requirements for cold chain storage and transportation.

A kind of microneedle preparation provided by the application is a microneedle patch. After application, the puncture ability and dissolubility are good; Dissolve within 240min, which indicates that the dissolution time of the patch can be selected according to the efficacy of the drug.

Compared with injection preparations, the microneedle transdermal patch provided by this application can achieve a substantially equivalent maximum blood drug concentration, and the time to reach the maximum blood drug concentration is effectively delayed, and the maximum concentration can be continuously maintained for 4-8 hours. Decrease slowly to achieve the effect of sustained drug release for a long time. In addition, the microneedle transdermal patch provided by the present application can effectively deliver drugs for the prevention and/or treatment of osteoporosis or related bone disorders (such as parathyroid hormone-related peptides, parathyroid hormone analogues, etc., further such as A Baparatide, etc.), can effectively increase bone mineral density in subjects with osteoporosis.

Description of drawings

In order to more clearly illustrate the technical solutions in the embodiments of the present application, and to understand the present application and its beneficial effects more completely, the following briefly introduces the drawings that need to be used in the description of the embodiments. Apparently, the drawings in the following description are only some embodiments of the present application, and those skilled in the art can obtain other drawings according to these drawings without creative efforts.

Fig. 1 is a 10% PVP K60 microneedle patch figure in an embodiment of the present application; A is a microneedle topography, and B is a microneedle array photo;

Fig. 2 is the dissolving test figure of the microneedle patch of 10%PVP K90 base material in different time points in an embodiment of the present application;

Fig. 3 is a microneedle topography diagram of the degree of dissolution of the microneedle patch at different times in an embodiment of the present application;

Fig. 4 is a diagram of the shape of the needle body of the microneedle patch of the PVP and Dex composite substrate according to an embodiment of the present application;

Fig. 5 is the puncture ability test diagram of the microneedle patch shown in Fig. 4;

Fig. 6 is the dissolution test diagram of the microneedle patch shown in Fig. 4 at different time points;

Fig. 7 is a test chart of 10% HA (5W) substrate in an embodiment of the present application; A is a picture of the needle body formation of the microneedle patch; B is a test chart of puncture ability;

Fig. 8 is the dissolution test diagram of the microneedle patch of 10% HA (5W) substrate in different time points in an embodiment of the present application;

Fig. 9 is the puncture capability test chart of the abaloparatide microneedle patch prepared in Example 5 of the present application;

Fig. 10 is the appearance diagram of different time points during the dissolution test of the microneedle patch of Fig. 9;

Fig. 11 is the microneedle morphology diagram at different time points during the dissolution test of the microneedle patch of Fig. 9;

Fig. 12 is a puncture ability test chart of 8% PVP K90+1% Dex+12.5mg/g abaloparatide microneedle patch in an embodiment of the present application;

Fig. 13 is the rat pharmacokinetic curve diagram of an embodiment of the present application, the horizontal axis (Time) is the sampling time point after administration, and the vertical axis (Plasma Concentration) corresponds to the drug concentration in plasma, corresponding to 40 μg/rat transdermal medication;

Figure 14 is a comparison chart of the time-varying blood concentration curves of abaloparatide microneedle transdermal patch MAP and injection formulation SC in one embodiment of the present application;

Fig. 15 is a graph showing changes in total hip BMD of osteoporosis model rats treated with abaloparatide microneedle transdermal patch in an embodiment of the present application.

Detailed ways

The present application will be further described in detail below in conjunction with the accompanying drawings, implementation modes and examples. It should be understood that these implementations and examples are only used to illustrate the present application and are not intended to limit the scope of the application. The purpose of providing these implementations and examples is to make the disclosure of the application more thorough and comprehensive. It should also be understood that the present application can be implemented in many different forms, and is not limited to the implementation modes and examples described herein. Those skilled in the art can make various changes or modifications without violating the connotation of the present application to obtain The equivalent forms also fall within the protection scope of the present application. Furthermore, in the following description, numerous details are given in order to provide a fuller understanding of the application, and it is understood that the application may be practiced without one or more of these details.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the technical field to which this application belongs. The terms used herein in the specification of the application are for the purpose of describing the embodiments and examples only, and are not intended to limit the application.

the term

Unless otherwise stated or contradictory, terms and phrases used herein have the following meanings:

As used herein, the terms "and/or", "or/and", "and/or" include any one of two or more of the associated listed items, and any of the associated listed items. and all combinations including any combination of any two of the relevant listed items, any more of the relevant listed items, or all of the relevant listed items. It should be noted that when at least three items are connected with at least two conjunctions selected from "and/or", "or/and", "and/or", it should be understood that in this application, the technical solution Undoubtedly include the technical solutions that are all connected by "logic and", and also undoubtedly include the technical solutions that are all connected by "logic or". For example, "A and/or B" includes three parallel schemes of A, B and "combination of A and B". For another example, the technical solution of "A, and/or, B, and/or, C, and/or, D" includes any one of A, B, C, and D (that is, all are connected by "logic or") technical solution), also includes any and all combinations of A, B, C, and D, that is, includes any combination of any two or any three of A, B, C, and D, and also includes A, B, and C , four combinations of D (that is, all use the technical scheme of "logic and" connection).

In this application, when at least three features are connected with at least two conjunctions selected from "and/or", "or/and", "and/or", it is equivalent to "having one or more features" An expression, for example, "TA, and/or, TB, and/or, TC, and/or, TD" is equivalent to "has one or more of the following features: TA, TB, TC and TD".

The present application refers to "multiple", "multiple", and "multiple times", etc., unless otherwise specified, means that the number is greater than 2 or equal to 2. For example, "one or more" means one or more than two.

In this application, unless otherwise stated, "one or more" means any one of the listed items or any combination of the listed items. Similarly, "one or more" and other expressions of "one or more" should be understood in the same way unless otherwise specified.

As used herein, "combinations thereof", "any combination thereof", "any combination thereof" and the like include all suitable combinations of any two or more of the listed items.

In this article, "suitable" mentioned in "suitable combination", "suitable way", "any suitable way" and so on can implement the technical solutions of the application, solve the technical problems of the application, and realize the expectations of the application. The technical effect shall prevail.

As used in this application, the terms "having", "comprising", "comprising" and "comprising" are synonyms, which are inclusive or open-ended and do not exclude additional, non-recited members, elements or method steps.

Herein, "preferred", "better", "better", "advisable", "for example", "such as", "example", and "example" are only descriptions of better or more detailed implementations or an embodiment, which means that the previous and later different technical solutions are related in terms of coverage, but it should be understood that it does not constitute a limitation on the protection scope of the present application. If there are multiple "preferences" in a technical solution, unless otherwise specified, and there is no conflict or mutual restriction relationship, each "preference" is independent. In this application, unless otherwise stated, A (such as B) means that B is a non-limiting example of A, and it can be understood that A is not limited to B.

In the present application, "further", "further", "particularly" and the like are used for description purposes, indicating differences in content, but should not be construed as limiting the protection scope of the present application.

In the present application, "optionally", "optionally" and "optionally" refer to dispensable, that is to say, any one selected from the two parallel schemes of "with" or "without". If there are multiple "optional" in a technical solution, unless otherwise specified, and there is no contradiction or mutual restriction relationship, each "optional" is independent. In the present application, descriptions such as "optionally contain" and "optionally contain" mean "contain or not contain". "Optional component X" means that component X is present or absent.

In this application, in "first aspect", "second aspect", "third aspect", "fourth aspect", etc., the terms "first", "second", "third", "fourth" etc. are for descriptive purposes only and shall not be understood as indicating or implying relative importance or quantity, nor as implying the importance or quantity of the indicated technical features. Moreover, "first", "second", "third", "fourth" and so on are only for the purpose of non-exhaustive enumeration and description, and it should be understood that they do not constitute a closed limitation on the quantity.

In this application, the technical features described in open form include closed technical solutions consisting of the listed features, and open technical solutions including the listed features.

In this application, when it comes to numerical intervals (that is, numerical ranges), if there is no special description, the optional numerical values are distributed among the above numerical values Intervals are considered continuous and include the two numerical endpoints (ie, minimum and maximum) of the numerical range, and every value between those two numerical endpoints. Unless otherwise specified, when the numerical range refers only to the integers within the numerical range, including the integers at the two endpoints of the numerical range, and every integer between the two endpoints, in this article, it is equivalent to directly enumerating each An integer, such as t being an integer selected from 1 to 10, means that t is any integer selected from the integer group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. Furthermore, when multiple ranges are provided to describe a feature or characteristic, these ranges may be combined. In other words, unless otherwise indicated, ranges disclosed herein are to be understood to include any and all subranges subsumed therein.

In this application, whenever a numerical value or a numerical range is involved, unless otherwise specified, it should be understood that the numerical range covers a reasonable submultiple of the two endpoints, and those skilled in the art can understand that the fluctuation range brought about by the submultiple can be included to within the interval covered by the indicated numerical range. That is to say, in this application, unless otherwise stated, "N1" and "about N1" have the same meaning and can be used interchangeably, and "N1～N2" and "about N1 to about N2" have the same meaning and can be used interchangeably , wherein, N1 and N2 are two unequal values; due to one or more factors such as reasonable deviations allowed in this field, instrument control accuracy, etc., the approximate values within the range of approximate numbers should also be included in the range of values within the scope of the guidelines. For example, "the temperature is 20°C to 30°C" can be understood as "about 20°C to about 30°C"; further, taking the endpoint as "20°C" and its approximation as ±1°C as an example, "about 20°C Approximate values such as 19°C and 19.5°C within the approximation range shown in " should also be included in the range guided by 20°C to 30°C.

In the present application, an approximation (such as "about 20") is involved. If there is no special limitation, the fluctuation range is generally ±10%, and may further refer to ±8%, ±5%, ±3%, etc. Approximate numbers in this application provide both the listed value and the range of values represented by the approximate number. For example, about 500Da not only provides the technical solution of "500Da", but also provides the technical solution of "500Da±fluctuation range".

The temperature parameters in this application, unless otherwise specified, are allowed to be treated at a constant temperature, and are also allowed to vary within a certain temperature range. It should be understood that the isothermal treatment described allows the temperature to fluctuate within the precision of the instrument control. It is allowed to fluctuate within the range of ±5°C, ±4°C, ±3°C, ±2°C, ±1°C.

In the present application, the term "room temperature" generally refers to 4°C to 35°C, and a preferred mode is 20°C±5°C. In some embodiments of the present application, the room temperature refers to 20°C to 30°C.

All documents mentioned in this application are incorporated by reference in this application as if each individual document were individually indicated to be incorporated by reference. Unless it conflicts with the invention purpose and/or technical solution of the application, the cited documents involved in the application are cited in their entirety and for all purposes. When referring to cited documents in this application, the definitions of relevant technical features, terms, nouns, phrases, etc. in the cited documents are also cited. When citing documents are involved in this application, the examples and preferred modes of the cited related technical features can also be incorporated into this application as a reference, but only if the application can be implemented. It should be understood that when the referenced content conflicts with the description in the present application, the present application shall prevail or be amended adaptively according to the description in the present application.

The mass or weight of the relevant components mentioned in this application can not only refer to the specific content of each component, but also represent the proportional relationship between the mass or weight of each component. Therefore, as long as it is according to the relevant components in this application The scaling up or down of the content is within the scope provided by the present application. Specifically, the mass or weight described in the present application may be μg, mg, g, kg and other well-known units in the field of chemical engineering.

In the present application, where multiple steps are involved in the method flow, unless there is a clear different description herein, the execution of these steps is not strictly limited to the order, and they can be executed in an order other than the one described. Moreover, any step may include a plurality of sub-steps or stages, and these sub-steps or stages are not necessarily executed at the same time, but may be executed at different times, and the order of execution is not necessarily sequential, but It can be performed in turn or alternately with other steps or sub-steps of other steps or a part of stages, or at the same time.

In this article, when referring to the unit of the data range, if there is only a unit after the right endpoint, it means that the units of the left endpoint and the right endpoint are the same. For example, 1-200 μm means that the units of the left endpoint 1 and the right endpoint 200 are both micrometers.

Herein, the term "derivative" refers to a compound having a similar structure formed from a basic compound through chemical changes. The aforementioned chemical changes include, but are not limited to: ionization, deionization, complexation, decomplexation, hydration, dehydration, esterification, oxidation, reduction, electron rearrangement, structural rearrangement, protection, deprotection (activation), etc. Chemical changes. After the base compound undergoes a derivatization reaction, at least one of function and activity may be changed. Herein, "isofunctional derivative" means a compound that, after derivatization, still has the same function as the base compound through basically the same mechanism. In terms of activity, it can be slightly lower, similar (including basically the same) or better. The "same function" in this article includes at least the same function in a given disease category, for example, the isofunctional derivative of abaloparatide refers to the derivative obtained from the basic compound of abaloparatide, and the derivative The therapeutic effect of preventing and/or treating osteoporosis or its related bone disorders is exerted by basically the same mechanism as that of abaloparatide. Herein, "substantially the same activity" means that there is no pharmaceutically acceptable significant difference in activity. Here, "the therapeutic effect of preventing and/or treating osteoporosis or its related bone disorders" means the therapeutic effect of preventing osteoporosis or its related bone disorders, the therapeutic effect of treating osteoporosis or its related bone disorders , and any one of the therapeutic effects of preventing and treating osteoporosis or its related bone diseases. In this application, "prevention" is taken as an example. Unless otherwise specified, preventing osteoporosis or its related bone diseases means preventing at least one of osteoporosis and osteoporosis-related bone diseases.

In the present application, unless otherwise stated, "osteoporosis", "osteoporosis and its related bone disorders" and "osteoporosis or its related bone disorders" have the same scope of meaning.

A derivative form of the polypeptide in the present application is that one or more amino acid units are added to at least one of the N-terminal and C-terminal of the polypeptide, but the activity remains basically the same or better or only slightly decreased. "Slightly lower" or "slightly decreased" means that the effect is less than that of the original compound from which it was derived, but still meets the therapeutic needs.

Herein, the term "analogue", unless otherwise specified, refers to "similar analogue", which means that although it is not derived from the reference compound in structure, it can exert the same function compared to the reference compound, And compounds with slightly lower, similar (including substantially the same) or better activity effects. For those skilled in the art, as long as the reference compound is determined, it is possible to tell whether a certain compound belongs to the category of "analogue" of the present application through the effect test. Therefore, the "analogue" of the present application is clear.

Herein, "drug" includes any agent, compound, composition or mixture that provides at least one of physiological and pharmacological effects in vivo or in vitro, and often provides beneficial effects. The range of at least one of physiological and pharmacological effects produced by the "drug" in the body is not particularly limited, and may be systemic or local. The activity of the "drug" is not particularly limited, and it may be an active substance that can interact with other substances, or an inert substance that does not interact.

As used herein, "treating" refers to alleviating, delaying progression, attenuating, or maintaining an existing disease or condition (eg, cancer). Treatment also includes curing, preventing its development, or alleviating to some extent one or more symptoms of a disease or disorder.

Herein, "therapeutically effective amount" refers to the amount of an active pharmaceutical ingredient that will cause a biological or medical response in an individual, for example, an amount of an active pharmaceutical ingredient that will bring about at least one physiologically and pharmacologically positive effect on an individual, said Physiologically and pharmacologically at least one positive effect includes, but not limited to, reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing down or delaying disease progression or preventing diseases, etc.

Herein, "pharmaceutically acceptable" refers to any one or any combination of those ligands, materials, compositions and dosage forms that are suitable for administration to a patient within the scope of sound medical judgment and commensurate with a reasonable benefit/risk ratio.

In this application, "pharmaceutical excipient" and "pharmaceutically acceptable excipient" have the same meaning and can be used interchangeably.

Herein, "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. As used herein, the language "pharmaceutically acceptable carrier" includes buffers, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorbing agents compatible with pharmaceutical administration Retardants and the like. Each carrier must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Suitable examples include, but are not limited to: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch, potato starch, and substituted or unsubstituted beta-cyclodextrins; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyhydric Alcohols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) Esters, such as ethyl oleate and ethyl laurate; (13) Agar; (14) Buffers, such as magnesium hydroxide and hydrogen (15) Alginic acid; (16) Pyrogen-free water; (17) Isotonic saline; (18) Ringer's solution; (19) Ethanol; (20) Phosphate buffered saline; and (21) Drug formulation Other non-toxic compatible substances used in the product.

Any of the formulations herein may each independently contain one or more conventional inert excipients (or carriers), such as sodium citrate or dicalcium phosphate, or be mixed with: (a) fillers or extenders Agents such as starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c ) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin (f) absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as , talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof.

Herein, "subject" refers to an animal, preferably a mammal, and further preferably a human. As used herein, "patient" refers to an animal, preferably a mammal, and further preferably a human. The term "mammal" primarily refers to warm-blooded vertebrate mammals, including but not limited to cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice, pigs, cows, sheep, horses and humans.

The polyvinylpyrrolidone (Polyvinylpyrrolidone, PVP, also referred to as polyvinylpyrrolidone) used herein is a non-ionic polymer. Such as the K value in PVP K12, PVP K15, etc. is a characteristic value related to the relative viscosity of the PVP aqueous solution, and the viscosity is a physical value related to the molecular weight of the polymer. Therefore, the K value can be used to characterize the average molecular weight of PVP. . Generally speaking, the larger the K value, the greater the viscosity.

Table 1. The relationship between K value and average molecular weight of polyvinylpyrrolidone used in the present application

Herein, the molecular weight of a "substance" refers to the average molecular weight unless otherwise specified; for a monodisperse substance, its molecular weight value is definite, and its molecular weight can be regarded as the average molecular weight. Furthermore, unless otherwise specified, it refers to a weight average molecular weight. The "substance" may be a polymer, further including a hydrophilic polymer.

In this application, "small molecule" means that the molecular weight does not exceed 1000Da (i.e. ≤ 1000Da), unless it is specifically limited. "Low molecular weight" is used to define different substances and corresponds to different ranges. "Polymer" means a molecular weight greater than 1000 Da. Further, unless otherwise stated, it refers to the weight average molecular weight.

Herein, a macromolecular sugar refers to a sugar with a molecular weight greater than 1000 Da. Further, it refers to sugars with a weight average molecular weight greater than 1000Da.

Herein, "carbohydrate" is a compound composed of carbon, hydrogen and oxygen, and it should be understood that it is limited to those carbohydrates that can be used in this application. Carbohydrates can be sugars. Herein, sugars include monosaccharides, disaccharides, and polysaccharides, and may include, for example, non-reducing sugars such as raffinose, stachyose, sucrose, and trehalose; and reducing sugars such as monosaccharides and disaccharides; exemplary Monosaccharides include but are not limited to apiose, arabinose, digitoxanose, fucose, fructose, galactose, glucose, gulose, witch hazel sugar, idose, lyxose, mannose, ribose , tagatose, sorbitol, xylitol and xylose. Exemplary disaccharides include, but are not limited to, sucrose, trehalose, cellobiose, gentiobiose, lactose, lactulose, maltose, melibiose, primrose, rutinose, mariobiose, sophorbiose sugar, turanose, and pobiose. In some embodiments, sucrose, trehalose, fructose, maltose, or combinations thereof may be utilized. All optical isomers (D, L and racemic mixtures) of the exemplified sugars are also included herein. Exemplary polysaccharides include starches such as hydroxyethyl starch, pregelatinized corn starch, starch, dextrin, dextran or dextran sulfate, gamma-cyclodextrin, alpha-cyclodextrin, beta-cyclodextrin , Glucosyl-α-cyclodextrin, Maltosyl-α-cyclodextrin, Glucosyl-β-cyclodextrin, Maltosyl-β-cyclodextrin, 2-Hydroxy-β-cyclodextrin, 2 -Hydroxypropyl-β-cyclodextrin, 2-hydroxypropyl-γ-cyclodextrin, hydroxyethyl-β-cyclodextrin, methyl-β-cyclodextrin, sulfobutyl ether-α- Cyclodextrin, sulfobutyl ether-β-cyclodextrin, and sulfobutyl ether-γ-cyclodextrin. In some embodiments, hetastarch, dextrin, dextran, gamma-cyclodextrin, beta-cyclodextrin, or combinations thereof may be utilized. In some embodiments, dextran having an average molecular mass of 35,000 to 76,000 g/mol may be utilized. In some embodiments, the at least one carbohydrate is cellulose. Suitable celluloses include, but are not limited to, hydroxyethyl cellulose (HEC), methyl cellulose (MC), microcrystalline cellulose, hydroxypropyl methyl cellulose (HPMC), hydroxyethyl methyl cellulose (HEMC ), hydroxypropyl cellulose (HPC), and mixtures thereof.

Herein, "amino acid" can be natural amino acid or unnatural amino acid, and can be _L -form, _D -form or _L / _D form. "Amino acid" as used herein may be selected from: including but not limited to glycine, alanine, valine, leucine, isoleucine, phenylalanine, proline, sarcosine, serine, threonine amino acid, cysteine, methionine, tyrosine, aspartic acid, glutamic acid, asparagine, glutamine, lysine, arginine, histidine, tryptophan, Hydroxyproline, ornithine, etc.

Herein, "peptide bond" refers to the "C(=O)-N" bond formed by removing a molecule of water between two amino acids.

Herein, polypeptides and proteins are multiple (≥2) amino acids refer to compounds formed by sequential linkage of peptide bonds. Herein, generally, the number of amino acid residues of the polypeptide is ≤200, further can be ≤150, further ≤100, and the number of amino acid residues of the protein is ≥50, further can be ≥100, further ≥150, further ≥200. When a polypeptide and a protein appear in the same definition, optionally, the number of amino acid residues of the polypeptide is ≤100, and the number of amino acid residues of the protein is ≥100.

The first aspect of the application

In the first aspect of the present application, a pharmaceutical composition is provided, comprising the following components: a first active ingredient, an optional penetration-promoting ingredient, a polymer substrate ingredient, an optional first functional ingredient, an aqueous solvent, and an optional The selected organic solvent can also include one or more of the following optional components: solubilizer, bacteriostat, suspending agent and the Nth adjuvant; the first active ingredient is to prevent and/or treat osteoporosis or A drug for related bone disorders; the first functional ingredient is a protective agent and/or a dissolution accelerator. The pharmaceutical composition contains an active ingredient (referred to as the first active ingredient) capable of preventing and/or treating osteoporosis or related bone diseases, and each component cooperates with each other to form a whole, and can be made into a medicinal Microneedles, pharmaceutical preparations (such as microneedle preparations), microneedle drug delivery systems, etc., are used to prevent and/or treat osteoporosis or related bone diseases. Compared with the single administration method of traditional macromolecular pharmaceutical preparations (such as subcutaneous injection), the active ingredients in the pharmaceutical composition can be administered through the skin, which avoids the problems of poor patient compliance caused by injection and does not affect the drug. Advantages of absorption.

In this application, unless otherwise stated, "prevention and/or treatment" means all or any of prevention, treatment and "prevention and treatment". According to the logical relationship of semantics, it can be all situations of prevention, treatment and "prevention and treatment", or any situation of prevention, treatment and "prevention and treatment".

In this application, unless otherwise stated, "prevention and/or treatment of osteoporosis or related bone disorders" means, (i) prevention of osteoporosis or related bone disorders, (ii) treatment of osteoporosis or related bone disorders Bone disorders and (iii) concurrent prevention and treatment of all or any of osteoporosis or related bone disorders.

In the present application, unless otherwise specified, "osteoporosis or related bone disorders" means at least one of "osteoporosis" and "osteoporosis-related bone disorders".

In this application, unless otherwise stated, "drugs for preventing and/or treating osteoporosis or related bone disorders" means drugs for preventing osteoporosis or related bone disorders, treating osteoporosis or related bone disorders Drugs for the prevention and treatment of osteoporosis or related bone disorders. "The first active ingredient is a drug for preventing and/or treating osteoporosis or related bone disorders" means that the first active ingredient is a drug for preventing osteoporosis or related bone disorders, or treating osteoporosis or related bone disorders Any of the drugs for the prevention and treatment of osteoporosis or related bone disorders at the same time.

In this application, unless otherwise specified, "the pharmaceutical composition contains an active ingredient (referred to as the first active ingredient) capable of preventing and/or treating osteoporosis or related bone diseases", which means that the pharmaceutical composition At least one of active ingredients capable of preventing osteoporosis or related bone disorders, active ingredients capable of treating osteoporosis or related bone disorders, and active ingredients capable of preventing and treating osteoporosis or related bone disorders . It can be understood that the first active ingredient is an active ingredient capable of preventing osteoporosis or related bone disorders, an active ingredient capable of treating osteoporosis or related bone disorders, an active ingredient capable of preventing and treating osteoporosis or related bone disorders any of the ingredients.

In this application, unless otherwise stated, the term "osteoporosis" when used alone includes osteoporosis and related bone disorders, for example, prevention and/or treatment of osteoporosis, including prevention and/or treatment of osteoporosis Osteoporosis-related bone disorders, as long as the prevention and/or treatment of the related bone disorders can promote the prevention and/or treatment of osteoporosis.

In this application, unless otherwise stated, "protective agent and/or dissolution accelerator" means a protective agent, dissolution accelerator or a combination thereof. "The first functional component is a protective agent and/or a dissolution accelerator" means that the first functional component may have either function of a protective agent or a dissolution accelerator, or both functions.

In some embodiments, the pharmaceutical composition of the first aspect includes the following components in parts by weight:

in,

The first active ingredient is a drug for the prevention and/or treatment of osteoporosis or related bone disorders;

The first functional ingredient is a protective agent and/or a dissolution accelerator;

The organic solvent is a pharmaceutically acceptable organic solvent;

Optionally, the total parts by weight of the pharmaceutical composition is 100 parts.

In some embodiments, based on 100 parts by weight of the total pharmaceutical composition, the parts by weight of the first active ingredient are 0.01-15 parts by weight, and the parts by weight of the water-soluble solvent are 50-90 parts by weight.

In some embodiments, the pharmaceutical composition of the first aspect further includes one or more of the following components: solubilizer, bacteriostat and suspending agent.

In some embodiments, in parts by weight, the pharmaceutical composition of the first aspect includes the following components: 0.01-18 parts (further such as 0.01-15 parts) of the first active ingredient, 0-5 parts of the penetration-promoting component, and a high 1-50 parts of the molecular substrate component, 0-5 parts of the first functional component, 40-90 parts of the aqueous solvent (further such as 50-90 parts) and 0-5 parts of the organic solvent, and may also include one or more of the following Optional components: solubilizer, antibacterial agent, suspending agent and Nth auxiliary material; wherein, the total weight part of the pharmaceutical composition is 100 parts.

In some embodiments, the pharmaceutical composition of the first aspect further includes the following components:
0-5 parts of solubilizer;
Bacteriostatic agent 0-1 part; and suspending agent 0-10 part;

Wherein, the weight part of at least one of the solubilizer, the bacteriostat and the suspending agent is not zero.

In some embodiments, the pharmaceutical composition of the first aspect further includes an Nth auxiliary material; the Nth auxiliary material is a component different from the penetration-promoting component, the polymer substrate component, the first functional component, an aqueous solvent, an organic solvent, and a solubilizer , pharmaceutical excipients for antibacterial agents and suspending agents.

In some embodiments, the weight part of the Nth auxiliary material is 0-10 parts, but not 0 parts.

In some embodiments, the Nth auxiliary material is selected from one or more of the following group: pH regulator, plasticizer, magnesium agent, zinc agent wait.

In some embodiments, the pharmaceutical composition includes a pH adjusting agent.

In some embodiments, the pharmaceutical composition of the first aspect includes the following components in parts by weight:

in,

The total parts by weight of the pharmaceutical composition is 100 parts;

The first active ingredient is a drug for the prevention and/or treatment of osteoporosis or related bone disorders;

The first functional ingredient is a protective agent and/or a dissolution accelerator;

The organic solvent is a pharmaceutically acceptable organic solvent, which is recorded as the first organic solvent;

The Nth excipient is a pharmaceutical excipient different from any of the aforementioned ingredients.

first active ingredient

The first active ingredient is a pharmaceutical ingredient in the pharmaceutical composition of the first aspect that can provide preventive and/or therapeutic effects on osteoporosis or related bone diseases. The first active ingredient can be selected from any existing preventive and/or therapeutic drugs for osteoporosis or related bone diseases, including but not limited to literature reports, marketing, public disclosure, etc.

Osteoporosis is mainly caused by an imbalance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption.

In some embodiments, the associated bone disorder includes one or more of osteopenia, osteoarthritis, and bone fracture.

In some embodiments, the first active ingredient is selected from one or more of the following group: anti-bone resorption agent, bone-promoting agent, bone morphogenetic protein 9, activin A, semaphorin 3A, calcium agent, vitamin D , strontium, estrogen drugs, selective estrogen receptor modulators, pharmaceutically acceptable salts of any of the foregoing, isomorphic derivatives of any of the foregoing, and isomorphic analogs of any of the foregoing, and Any of the aforementioned markers. In this application, "any of the foregoing" allows for nested definitions. Taking this as an example, the isofunctional derivatives of any of the aforementioned include both the aforementioned bone resorption inhibitors, bone formation-promoting agents, bone morphogenetic protein 9, activin A, semaphorin 3A, calcium, vitamin D, strontium , estrogen drugs, and selective estrogen receptor modulators, and also include "pharmaceutically acceptable salts of any of the aforementioned" derivatives, "any of the aforementioned The same functional analogs of ", "any of the foregoing" in "markers of any of the foregoing", and "any of the foregoing" in other parts of this application should be understood in the same way.

In some embodiments, the bone resorption inhibitors include bisphosphonates (Bisphosphonates), nuclear factor-κB receptor activator ligand monoclonal antibody (RANKL monoclonal antibody), cathepsin K inhibitor, Src kinase inhibitor , IKKβ inhibitor, p38MAPK inhibitor, calcitonin, etc., a pharmaceutically acceptable salt of any of the foregoing, an isomorphic derivative of any of the foregoing, an isomorphic analog of any of the foregoing, and any of the foregoing One or more of the species markers.

In some embodiments, the osteogenic agent includes parathyroid hormone, parathyroid hormone-related peptide (PTHrP), parathyroid hormone analogs, parathyroid hormone activators, calcium-sensing receptor antagonists, sclerostin monoclonal Cloned antibody, DKK-1 monoclonal antibody, etc., pharmaceutically acceptable salts of any of the foregoing, isomorphic derivatives of any of the foregoing, isomorphic analogs of any of the foregoing, and labels of any of the foregoing one or more of them.

In some embodiments, the first active ingredient is selected from one or more of the following group: parathyroid hormone, parathyroid hormone-related peptides, parathyroid hormone analogs, parathyroid hormone activators, any of the foregoing A pharmaceutically acceptable salt of any one of the foregoing, isofunctional derivatives of any of the foregoing, isofunctional analogs of any of the foregoing, and labels of any of the foregoing.

Examples of bisphosphonates include risedronate sodium, ibandronate sodium, alendronate sodium, zoledronic acid and the like.

Examples of RANKL monoclonal antibodies are denosumab and Dnosumab.

Examples of cathepsin K inhibitors include odanacatib.

Examples of Src kinase inhibitors include sarcatinib and saratinib.

Examples of IKKβ inhibitors include: IMD0354.

Examples of p38MAPK inhibitors include ADAM12, TAT-TN13 and SB239063.

Examples of calcitonin include elcatonin and miacalcic.

Parathyroid hormone Parathyroid hormone (PTH) is a single-chain polypeptide secreted by parathyroid chief cells. Parathyroid hormone increases DNA repair and inhibits osteoblast apoptosis, which can increase bone density in patients with osteoporosis and improve bone health. metabolic indicators.

Parathyroid hormone-related peptide (PTHrP) is a polypeptide substance that activates parathyroid hormone receptor 1 (PTHR1) to promote the differentiation and maturation of mesenchymal stem cells into osteoblasts and inhibit osteoblast differentiation. Osteoblast apoptosis eventually increases the number and function of osteoblasts. Examples of PTHrP include abaloparatide and teriparatide.

Abaloparatide (abaloparatide), a parathyroid hormone-related peptide (PTHrP), is a powerful selective activator of PTH-I receptors, which can increase bone mineral content, bone density and bone strength, and promote Bone formation, abaloparatide is a polypeptide composed of 34 amino acid residues, with a molecular formula of C ₁₇₄ H ₃₀₀ N ₅₆ O ₄₉ and a molecular weight of 3960.64Da. The amino acid sequence of abaloparatide is: Ala-Val-Ser-Glu-His-Gln-Leu-Leu-His-Asp-Lys-Gly-Lys-Ser-Ile-Gln-Asp-Leu-Arg-Arg-Arg -Glu-Leu-Leu-Glu-Lys-Leu-Leu-Aib-Lys-Leu-His-Thr-Ala- _NH2 .

Teriparatide (hPTH(1-34)), a synthetic polypeptide hormone, is a 1-34 amino acid fragment of human parathyroid hormone PTH, which is an endogenous parathyroid hormone containing 84 amino acids. The prime PTH has a biologically active N-terminal region. The amino acid sequence of teriparatide is:

H-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-Ser-Met-Glu-Arg-Val-Glu-Trp-Leu- Arg-Lys-Lys-Leu-Gln-Asp-Val-His-Asn-Phe-OH.

Examples of parathyroid hormone analogues (parathyroid hormone analogue, PTHa) are RGB-10 and the like.

An example of a parathyroid hormone activator is Abaloparatide.

Calcilytic receptor antagonists are exemplified by Calcilytic.

Examples of sclerostin monoclonal antibodies include Romosozumab.

Examples of DKK-1 monoclonal antibodies are Dickkopf-1 (DKK-1), secreted frizzled-related protein (sFrps).

Estrogenic drugs such as estradiol valerate.

In some embodiments, the first active ingredient is selected from one or more of the following group: parathyroid hormone, abaloparatide, teriparatide, abalatide, any of the pharmaceutically available Accepted salts, isomorphic derivatives of any of the foregoing, isomorphic analogs of any of the foregoing, and labels of any of the foregoing.

In this application, any homologous derivative independently has one or more of the following derivative forms: including but not limited to subunits, fragments, domains, dimers, multimers, mutants, protein derivatives substances, polypeptide derivatives, amino acid derivatives, nucleic acid derivatives, synthetic polymer derivatives, lipid derivatives, glycosylated derivatives, and those undergoing tagging, substitution, degrouping, hydrophilic modification, hydrophobic modification One or more derivative changes in properties, ionization, deionization, complexation, decomplexation, hydration, dehydration, esterification, oxidation, reduction, electron rearrangement, structural rearrangement, protection and deprotection Derivatives. Protein derivatives, polypeptide derivatives, amino acid derivatives, nucleic acid derivatives, synthetic polymer derivatives (such as polyethylene glycol derivatives), lipid derivatives, and glycosylated derivatives refer to grafted proteins, polypeptides, Derivatives formed from amino acids, nucleic acids, synthetic polymers, lipid molecules, and sugar groups.

In the present application, "mutant" refers to a compound having an amino acid sequence, a nucleotide sequence, or an amino acid sequence and a nucleotide sequence, and "mutation" refers to a sequence unit (amino acid, nucleotide or One or more sequence changes in insertions, knockouts, shifts, substitutions, additions, truncations, rearrangements, and combinations thereof).

In this application, any marker is independently selected from: including but not limited to fluorescent markers and isotopic markers.

In some embodiments, the first active ingredient is a traditional Chinese medicine composition. The traditional Chinese medicine composition used herein can be selected from existing traditional Chinese medicine compositions for preventing and/or treating osteoporosis or related bone diseases.

In some embodiments, based on 100 parts by weight of the pharmaceutical composition, the parts by weight of the first active ingredient are 0.01-18 parts, further 0.01-15 parts, further 0.1-15 parts, and further 0.5-15 parts. 15 parts, furthermore, 1 to 15 parts. The parts by weight of the first active ingredient are for example 0.01, 0.02, 0.04, 0.05, 0.1, 0.2, 0.4, 0.5, 0.6, 0.8, 1, 1.2, 1.4, 1.5, 1.6, 1.8, 2, 2.2, 2.4, 2.5, 2.6, 2.8, 3, 3.2, 3.4, 3.5, 3.6, 3.8, 4, 4.2, 4.5, 4.6, 4.8, 5, 5.5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 etc. parts by weight. Based on 100 parts by weight of the pharmaceutical composition, the parts by weight of the first active ingredient can also be in any of the following ranges: 0.1-18 parts, 0.5-18 parts, 1-18 parts, 5-18 parts, 8-18 parts , 9-18 parts, 0.1-17 parts, 0.5-17 parts, 1-17 parts, 5-17 parts, 8-17 parts, 9-17 parts, 0.5-15 parts, 1-15 parts, 5-15 parts , 8-15 parts, 9-15 parts, 0.1-12 parts, 0.5-12 parts, 1-12 parts, 5-12 parts, 8-12 parts, 9-12 parts, 1-10 parts, 5-10 parts , 8-10 parts, 10-18 parts, 10-17 parts, etc.

In some embodiments, the dry weight ratio of the first active ingredient in the pharmaceutical composition is 0.1% to 30%, and it can also be selected from any of the following percentages or the interval formed by any two percentages: 0.1%, 0.5% %, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, etc. The dry weight ratio of the first active ingredient in the pharmaceutical composition can also be selected from any of the following ranges: 1% to 30%, 5% to 30%, 10% to 30%, 10% to 15%, 15% %~25%, 25%~30%, etc.

Polymer substrate composition

In this application, the polymer substrate component is one of the essential carrier or excipient components. A hydrophilic polymer may be preferred.

In some embodiments, the hydrophilic polymer is selected from one or more of the following group: polyglycolic acid, polylactic acid, polylactic acid-glycolic acid copolymer, polyvinyl alcohol, polyethylene glycol and derivatives thereof , polypropylene glycol and its derivatives, polyvinylpyrrolidone, sodium hyaluronate, collagen, gelatin, cellulose, cellulose derivatives, macromolecular sugars, glycoproteins and proteoglycans. In some embodiments, the hydrophilic polymer is selected from one or more of the following group: polyglycolic acid, polylactic acid, polylactic acid-glycolic acid copolymer, polyvinyl alcohol, polyethylene glycol and derivatives thereof , polypropylene glycol and its derivatives, polyvinylpyrrolidone, sodium hyaluronate, collagen, gelatin, macromolecular sugars and their derivatives, glycoproteins and proteoglycans. The polyethylene glycol derivatives, polypropylene glycol derivatives, macromolecular sugars and derivatives thereof, and cellulose derivatives here should still have the required hydrophilicity.

Some non-limiting examples of macromolecular sugars and their derivatives are hyaluronic acid, cellulose and cellulose derivatives, dextran and its derivatives, and the like. In some embodiments, cellulose derivatives include, but are not limited to, carboxymethylcellulose, hydroxypropylcellulose, and sodium salts of any of the foregoing. In some embodiments, the macromolecular sugar is one or more of cellulose and dextran. In some embodiments, the macromolecular sugar is cellulose. In some embodiments, the macromolecular sugar is dextran. In some embodiments, the macromolecular sugar derivative is one or more of hyaluronic acid and its salts (such as sodium hyaluronate), and cellulose derivatives.

In some embodiments, the hydrophilic polymer is selected from polyvinylpyrrolidone (PVP), carboxymethylcellulose and its sodium salt, hydroxypropylcellulose and its sodium salt, polyvinyl alcohol, polyethylene glycol, transparent One or more of sodium hyaluronate, gelatin and macromolecule sugar.

In some embodiments, the polymer substrate component is a hydrophilic polymer, and further, the polymer substrate component is one or more of polyglycolic acid, polyvinylpyrrolidone, macromolecule sugar and its derivatives, etc. .

In some embodiments, the polymer substrate component includes polyvinylpyrrolidone, and further includes macromolecular sugar or its derivatives.

In some embodiments, the polymeric substrate component is polyglycolic acid.

In some embodiments, the polymeric substrate component is polyvinylpyrrolidone.

In some embodiments, the macromolecular substrate component is macromolecular sugar and its derivatives.

In some embodiments, the polymeric substrate component is a combination of polyglycolic acid and polyvinylpyrrolidone. In some embodiments, the polymer substrate component is a combination of polyglycolic acid and macromolecular sugar or derivatives thereof, that is, a combination of polyglycolic acid and macromolecular sugar, or a combination of polyglycolic acid and macromolecular sugar derivatives The combination. In some embodiments, the polymer substrate component is a combination of polyvinylpyrrolidone and macromolecular sugar or derivatives thereof, that is, a combination of polyvinylpyrrolidone and macromolecular sugar, or a combination of polyvinylpyrrolidone and macromolecular sugar derivatives The combination. In some embodiments, the polymer substrate component is a combination of polyglycolic acid, polyvinylpyrrolidone, macromolecular sugars and derivatives thereof. The macromolecule sugar or its derivatives may be as defined in any embodiment above and below herein.

In some embodiments, the weight average molecular weight of the macromolecular sugar and macromolecular sugar derivative is each independently greater than 1000 Da.

When the polymer substrate component is a combination of two hydrophilic polymers, they can be respectively recorded as the first polymer and the second polymer. The weight ratio of the first polymer to the second polymer can be selected from but not limited to the following ranges: 1:99 to 99:1, 1:(99～1), (1～99):1, 1:50 to 50:1, 1:(50～1), (1～50):1, 1:49 to 49:1, 1:(49～1), (1～49):1, 1:25 to 25: 1, 1:(25～1), (1～25):1, 1:24 to 24:1, 1:(24～1), (1～24):1, 1:20 to 20:1, 1:(20～1), (1～20):1, 1:19 to 19:1, 1:(19～1), (1～19):1, 1:10 to 10:1, 1:1: (10～1), (1～10):1, 1:9 to 9:1, 1:(9～1), (1～9):1, 1:5 to 5:1, 1:(5 ~1), (1~5):1, 1:4 to 4:1, 1:(4~1), (1~4):1, 1:3 to 3:1, 1:(3~1 ), (1～3):1, 1:2 to 2:1, 1:(2～1), (1～2):1, etc. Further, the weight ratio of the first polymer to the second polymer can also be selected from but not limited to any one or two of the following ratios: 1:99, 99:1, 1:89, 89 :1, 1:80, 80:1, 1:79, 79:1, 1:74, 74:1, 1:60, 60:1, 1:59, 59:1, 1:50, 50:1 , 1:49, 49:1, 1:40, 40:1, 1:30, 30:1, 1:29, 29:1, 1:24, 24:1, 1:20, 20:1, 1 :19, 19:1, 1:15, 15:1, 1:10, 10:1, 1:9, 9:1, 1:8, 8:1, 1:7, 7:1, 1:6 , 6:1, 1:5, 5:1, 1:4, 4:1, 1:3, 3:1, 2.5:1, 1:2.5, 1:2, 2:1, 1.5:1, 1 :1.5, 1:1, etc. The combination of the first polymer and the second polymer can be as defined in any of the examples herein. In some embodiments, the content of the first polymer is greater than or equal to the second polymer, that is, the weight ratio of the first polymer to the second polymer is ≥ 1, and can be selected from any suitable weight ratio or weight ratio range mentioned above . In some embodiments, the first polymer and the second polymer are selected from any two of polyglycolic acid, polyvinylpyrrolidone, macromolecular sugars and derivatives thereof. In some embodiments, the first polymer is polyvinylpyrrolidone. In some embodiments, the first polymer is polyglycolic acid. In some embodiments, the first polymer is a macromolecular sugar and its derivatives. In some embodiments, the second polymer is polyvinylpyrrolidone. In some embodiments, the second polymer is polyglycolic acid. In some embodiments, the second polymer is macromolecular sugar and its derivatives, and "macromolecular sugar and its derivatives" can be as defined in any of the contexts herein. In some embodiments, the first polymer is polyglycolic acid and the second polymer is polyvinylpyrrolidone. In some embodiments, the first polymer is polyglycolic acid and the second polymer is macromolecular sugar and its derivatives. In some embodiments, the first polymer is polyvinylpyrrolidone, and the second polymer is macromolecular sugar and its derivatives. In some embodiments, the first polymer is polyvinylpyrrolidone and the second polymer is polyglycolic acid. In any of the foregoing embodiments, "macromolecular sugars and their derivatives" can be as defined in any of the contexts herein, such as hyaluronic acid, cellulose and cellulose derivatives, dextran and its derivatives any of kind.

In some embodiments, the molecular weight of the hydrophilic polymer is greater than 1000 Da, and may preferably be > 5000 Da.

In some embodiments, the molecular weight of the hydrophilic polymer is 0.5-2 million Daltons, further 1-2 million Daltons, further 2-2 million Daltons. The molecular weight of the hydrophilic polymer is, for example, 5,000 Daltons, 10,000 Daltons, 20,000 Daltons, 30,000 Daltons, 40,000 Daltons, 50,000 Daltons, 60,000 Daltons, 70,000 Daltons, 80,000 Daltons, 90,000 Daltons, 100,000 Daltons, 150,000 Daltons, 200,000 Daltons, 250,000 Daltons, 300,000 Daltons, 350,000 Daltons Daltons, 400,000 Daltons, 450,000 Daltons, 500,000 Daltons, 550,000 Daltons, 600,000 Daltons, 650,000 Daltons, 700,000 Daltons, 750,000 Daltons 800,000 Daltons, 850,000 Daltons, 900,000 Daltons, 950,000 Daltons, 1 million Daltons, 1.1 million Daltons, 1.2 million Daltons, 1.3 million Daltons, 1.4 million Daltons, 1.5 million Daltons, 1.6 million Daltons, 1.8 million Daltons, 2 million Daltons, etc. The molecular weight of the hydrophilic polymer can also be selected from any of the following ranges: 4 to 2 million Daltons, 10 to 2 million Daltons, 200 to 1.8 million Daltons, 250 to 1.5 million Daltons, 4 ~900,000 Daltons, 40,000 to 600,000 Daltons, 40,000 to 100,000 Daltons, 40,000 to 60,000 Daltons, 45,000 to 58,000 Daltons, 250,000 to 500,000 Daltons, 27 to 40 10,000 Daltons, 1 to 1.5 million Daltons, etc.

In some embodiments, the molecular weight of the hydrophilic polymer is from 5 kDa to 1000 kDa. Examples of molecular weights of hydrophilic polymers are 1kDa, 1.5kDa, 2kDa, 2.5kDa, 3kDa, 3.5kDa, 4kDa, 4.5kDa, 5kDa, 5.5kDa, 6kDa, 6.5kDa, 7kDa, 7.5kDa, 8kDa, 8.5kDa, 9kDa, 9.5kDa, 10kDa, 11kDa, 12kDa, 13kDa, 14kDa, 15kDa, 16kDa, 17kDa, 18kDa, 19kDa, 20kDa, 25kDa, 30kDa, 35kDa, 40kDa, 45kDa, 50kDa, 55kDa, 60kDa, 70kDa, 80kDa, 90kDa, 100kDa , 200kDa , 300kDa, 400kDa, 500kDa, 600kDa, 700kDa, 800kDa, 900kDa, 1000kDa, etc. The molecular weight of the hydrophilic polymer can also be selected from any of the following ranges: 5～100kDa, 5～50kDa, 10～50kDa, 10～100kDa, 10～80kDa, 20～60kDa, 20～50kDa, 15～40kDa, 10 ～40kDa, 10～30kDa, 10～20kDa, 15～30kDa, etc.

In this context, 10,000 Daltons is equivalent to 10 kDa.

In some embodiments, the molecular weight of polyglycolic acid used as a polymer substrate component can be selected from any of the following ranges: 4 to 2 million Daltons, 100,000 to 2 million Daltons, 200,000 to 1.8 million Daltons Dalton, 250,000 to 1.5 million Daltons, 40,000 to 900,000 Daltons, 40,000 to 600,000 Daltons, 40,000 to 100,000 Daltons, 40,000 to 60,000 Daltons, 45,000 to 58,000 Daltons , 250,000 to 500,000 Daltons, 270,000 to 400,000 Daltons, 1 million to 1.5 million Daltons, etc. Polyvinylpyrrolidone used as a polymer substrate component may include any one or more of PVP K12, PVP K15, PVP K17, PVP K25, PVP K30, PVP K60, PVP K90, etc.

In some embodiments, the molecular weight of polyvinylpyrrolidone used as a polymer substrate component can be selected from any of the following ranges: 3 to 2 million daltons, 4 to 2 million daltons, 3 to 1.5 million daltons Dalton, 4-1.5 million Dalton, 10-2 million Dalton, 10-1 million Dalton, 200-1.8 million Dalton, 20-1.5 million Dalton, 250-1.5 million Dalton . ~600,000 Daltons, 40,000 to 100,000 Daltons, 40,000 to 60,000 Daltons, 45,000 to 58,000 Daltons, 250,000 to 500,000 Daltons, 270,000 to 400,000 Daltons, 100 to 150 Wan Dalton et al. In some embodiments, the molecular weight of polyvinylpyrrolidone used as a polymer substrate component may be 3-1.5 million Daltons, 4-1.5 million Daltons, 250-1.5 million Daltons, and the like.

In some embodiments, the molecular weight of the macromolecular sugar or its derivatives used as the polymer substrate component can be selected from any of the following ranges: 4-2 million Daltons, 4-1.5 million Daltons, 10 ~2 million Daltons, 100,000 to 1,000,000 Daltons, 200,000 to 1,800,000 Daltons, 200,000 to 1,500,000 Daltons, 250,000 to 1,500,000 Daltons, 100,000 to 1,000,000 Daltons, 200 to 100 10,000 Daltons, 500,000 to 1,000,000 Daltons, 600,000 to 1,000,000 Daltons, 500,000 to 800,000 Daltons, 40,000 to 900,000 Daltons, 40,000 to 600,000 Daltons, 40,000 to 100,000 Daltons Dalton, 40,000 to 60,000 Daltons, 45,000 to 58,000 Daltons, 250,000 to 500,000 Daltons, 270,000 to 400,000 Daltons, 1 million to 1.5 million Daltons, 5 to 100kDa, 5 to 50kDa , 10～50kDa, 10～100kDa, 10～80kDa, 20～70kDa, 20～60kDa, 20～50kDa, 15～40kDa, 10～40kDa, 10～30kDa, 10～20kDa, 15～30kDa, 50～100kDa, 50 ~80kDa etc. Non-limiting examples of macromolecular sugars or derivatives thereof used as components of the polymer substrate include hyaluronic acid or its salts, cellulose or its derivatives, dextran or its derivatives, and the like. In some embodiments, a non-limiting example of a macromolecular sugar or derivative thereof used as a component of the polymeric substrate is dextran. In some embodiments, the molecular weight of the macromolecule sugar or its derivatives used as the polymer substrate component may be 10-80 kDa, 20-70 kDa, etc.

In some embodiments, the molecular weight of dextran used as a polymer substrate component can be selected from any of the following ranges: 5-200kDa, 5-150kDa, 5-100kDa, 5-80kDa, 5-50kDa, 10 ～50kDa, 10～200kDa, 10～150kDa, 10～100kDa, 10～80kDa, 20～70kDa, 20～60kDa, 20～50kDa, 15～40kDa, 10～40kDa, 10～30kDa, 10～20kDa, 15～30kDa , 50-100kDa, 50-80kDa, etc. In some embodiments, the molecular weight of dextran used as a polymeric substrate component may be 10-80 kDa, 20-70 kDa, etc.

In some embodiments, the molecular weight of hyaluronic acid or its salt, cellulose or its derivatives used as the polymer matrix component can be selected from any of the following ranges: 4-2 million Daltons, 4-150 10,000 Daltons, 100,000 to 2,000,000 Daltons, 100,000 to 1,000,000 Daltons, 200,000 to 1,800,000 Daltons, 200,000 to 1,500,000 Daltons, 250,000 to 1,500,000 Daltons, 100,000 to 1,000,000 Daltons Dalton, 200,000 to 1,000,000 Daltons, 500,000 to 1,000,000 Daltons, 600,000 to 1,000,000 Daltons, 500,000 to 800,000 Daltons, 40,000 to 900,000 Daltons, 40,000 to 600,000 Daltons , 40,000 to 100,000 Daltons, 40,000 to 60,000 Daltons, 45,000 to 58,000 Daltons, 250,000 to 500,000 Daltons, 270,000 to 400,000 Daltons, 1 million to 1.5 million Daltons, etc.

In some embodiments, the first polymer is polyvinylpyrrolidone, the second polymer is macromolecular sugar or its derivatives, and the respective molecular weights can be selected from any suitable molecular weight herein.

In some embodiments, the first polymer is polyvinylpyrrolidone and the second polymer is dextran, each having a molecular weight selected from any suitable molecular weight herein.

In some embodiments, the polymer substrate component is a combination of polyvinylpyrrolidone and macromolecular sugar or its derivatives, and the respective molecular weights can be selected from any suitable molecular weight herein. Further, the macromolecular sugar or its derivatives can be selected from any suitable type mentioned above. In some embodiments, the macromolecular sugar or derivative thereof is dextran. At this time, the two macromolecular components cooperate with each other to provide better puncture performance and solubility for the microneedle preparation, and the macromolecular sugar or its derivatives can also play a role in protecting the active pharmaceutical ingredient (API); in addition, it can Provide better mechanical strength properties for microneedle preparations.

In some embodiments, the polymer substrate component is a combination of polyvinylpyrrolidone and dextran, and the microneedle preparation prepared based on this has a faster dissolution time of the microneedle and a quicker onset of action of the drug; the dextran can play a protective role. The role of the pharmaceutical ingredient (API); in addition, the mechanical strength of the formulation is high.

It should be understood that the molecular weight of the hydrophilic polymer has a certain upper limit to meet the solubility requirements of the pharmaceutical preparations prepared from the pharmaceutical composition. Taking the medicinal microneedles involved in this application, the microneedle preparations of the third aspect of this application, etc. as examples, the solubility of the microneedle body and the substrate requires that the hydrophilic polymer as the main carrier (or excipient) has a suitable solubility. sex.

In some embodiments, based on 100 parts by weight of the pharmaceutical composition, the parts by weight of the polymer substrate component are 1 to 50 parts, further 1 to 50 parts, further 5 to 50 parts, and further 10 parts by weight. ～50 parts, further 20～50. The parts by weight of polymer substrate components are for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 15, 16, 18, 20, 25, 30, 35, 40 , 45, 50 and other parts by weight. Based on 100 parts by weight of the pharmaceutical composition, the parts by weight of the polymer substrate component can also be selected from any of the following ranges: 1-45 parts, 1-30 parts, 1-25 parts, 1-20 parts, 1 ～15 parts, 1～10 parts, 5～45 parts, 5～30 parts, 5～25 parts, 5～20 parts, 5～15 parts, 5～10 parts, 8～45 parts, 8～30 parts, 8 ～25 parts, 8～20 parts, 20～50 parts, 25～50 parts, 25～45 parts, 30～50 parts, 30～45 parts, 35～50 parts, 35～45 parts, etc.

When the polymer matrix component is composed of the first polymer and the second polymer and the aforementioned two hydrophilic polymers, the parts by weight of any one of the hydrophilic polymers can be selected from 100 parts by weight of the pharmaceutical composition Appropriate ranges in the following ranges of parts by weight: 0.5 to 50 parts, 0.5 to 45 parts, 0.5 to 40 parts, 0.5 to 30 parts, 0.5 to 25 parts, 0.5 to 22 parts, 0.5 to 20 parts, 0.5 to 15 parts , 0.5-10 parts, 1-50 parts, 1-45 parts, 1-40 parts, 1-30 parts, 1-25 parts, 1-22 parts, 1-20 parts, 1-15 parts, 1-10 parts , 5-50 parts, 5-45 parts, 5-40 parts, 5-30 parts, 5-25 parts, 5-22 parts, 5-20 parts, 5-15 parts, 5-10 parts, 8-10 parts , 10-50 parts, 10-45 parts, 10-40 parts, 10-30 parts, 10-25 parts, 10-15 parts, 15-50 parts, 15-45 parts, 15-40 parts, 15-30 parts , 15-25 parts, 15-20 parts, 20-50 parts, 20-45 parts, 20-40 parts, 20-30 parts, 20-25 parts, etc. The weight ratio of the first polymer and the second polymer may be as defined previously. In some embodiments, based on 100 parts by weight of the pharmaceutical composition, the first polymer is 1-45 parts, and the second polymer is 0.1-40 parts; wherein, the parts by weight of the first polymer can also be selected from Any of the following ranges: 1-40 parts, 1-30 parts, 1-25 parts, 1-20 parts, 1-15 parts, 1-10 parts, 5-40 parts, 5-30 parts, 5-25 parts , 5-20 parts, 5-15 parts, 5-10 parts, 8-40 parts, 8-30 parts, 8-25 parts, 8-20 parts, 8-15 parts, 8-10 parts, 10-40 parts , 10-30 parts, 10-25 parts, 10-20 parts, 10-15 parts, 15-40 parts, 15-35 parts, 15-30 parts, 15-25 parts, 15-20 parts, 18-40 parts , 18～35 parts, 18～30 parts, 18～25 parts, 18～22 parts, 18～20 parts, 20～45 parts, 20～35 parts, 20～25 parts, etc., the weight parts of the second polymer It can also be selected from any of the following ranges: 0.5 to 40 parts, 0.5 to 30 parts, 0.5 to 25 parts, 0.5 to 20 parts, 0.5 to 15 parts, 0.5 to 10 parts, 0.5 to 8 parts, 0.5 to 5 parts, 0.5-4 parts, 0.5-3 parts, 0.5-2.5 parts, 0.5-2 parts, 1-40 parts, 1-30 parts, 1-25 parts, 1-20 parts, 1-15 parts, 1-10 parts, 1-8 parts, 1-5 parts, 1-4 parts, 1-3 parts, 1-2.5 parts, 1-2 parts, 5-40 parts, 5-30 parts, 5-25 parts, 5-20 parts, 5-15 parts, 5-10 parts, 5-8 parts, 10-40 parts, 10-30 parts, 10-25 parts, 10-20 parts, 10-15 parts, 15-40 parts, 15-35 parts, 15-30 parts, 15-25 parts, 15-20 parts, 18-40 parts, 18-35 parts, 18-30 parts, 18-25 parts, 18-22 parts, 18-20 parts, 20-45 parts, 20-35 copies, 20-25 copies, etc.

Penetration enhancer

The penetration-enhancing ingredient interacts with stratum corneum lipids to change its arrangement to enhance the penetration and absorption of the drug (the first active ingredient) on the skin.

In this application, the penetration-enhancing component is optional, that is, dispensable.

In some embodiments, the pharmaceutical composition of the first aspect does not contain a penetration enhancing component.

In some preferred embodiments of the present application, the pharmaceutical composition of the first aspect contains a penetration enhancing component.

In some embodiments, the penetration-promoting component is selected from one or more of the following group: surfactant (referred to as the first surfactant), dimethyl sulfoxide and its analogs, azone compounds, pyrrolidone Derivatives, alcohol compounds, fatty acid compounds and penetration enhancing peptides.

In some embodiments, the penetration enhancing component is selected from one or more of the following group: N-(8-(2-hydroxybenzoyl)amino) caprylate, N-methyl-2-pyrrolidone, nitrogen Ketones, Dimethyl Sulfoxide, Propylene Glycol, Ethanol, and Menthol.

Penetration-promoting peptides are peptides with a permeation-promoting effect. They are short peptides with less than 30 amino acid residues, which can promote polypeptides, proteins, nucleic acids, nanoparticles and other biologically active molecules to penetrate cell membranes or skin and play biological roles.

As the alcohol compound of the permeation-promoting component, the preferred molecular weight ≤ 1000, the preferred molecular weight ≤ 800, the preferred molecular weight ≤ 600, the preferred molecular weight ≤ 500, the molecular weight ≤ 400, and the Molecular weight ≤ 300, further molecular weight ≤ 200. Non-limiting examples of alcoholic compounds are propylene glycol, ethanol, and menthol.

In some embodiments, based on 100 parts by weight of the pharmaceutical composition, the parts by weight of the penetration-promoting component are 0.05-5 parts, further 0.1-5 parts, further 0.5-5 parts, and further 1-5 parts share. The parts by weight of the penetration-promoting component are for example 0.05, 0.1, 0.2, 0.4, 0.5, 0.6, 0.8, 1, 1.2, 1.4, 1.5, 1.6, 1.8, 2, 2.2, 2.4, 2.5, 2.6, 2.8, 3, 3.2 , 3.4, 3.5, 3.6, 3.8, 4, 4.2, 4.5, 4.6, 4.8, 5 parts by weight.

first functional ingredient

In this application, the first functional component is optional, that is, dispensable.

In some embodiments, the pharmaceutical composition of the first aspect does not contain the first functional ingredient.

In some preferred embodiments of the present application, the pharmaceutical composition of the first aspect contains the first functional ingredient.

The first functional component is a protective agent and/or a dissolution accelerator, that is, the first functional component should have at least one function of protecting the drug component and promoting the dissolution of the drug component. In the present application, unless otherwise specified, the pharmaceutical ingredients refer to drugs for the prevention and/or treatment of osteoporosis or related bone diseases.

In some embodiments, the first functional ingredient has a protective effect on the first active ingredient.

In some embodiments, the first functional ingredient has a dissolution-promoting effect on the first active ingredient.

In some embodiments, the first functional component also acts as a protective agent and/or a dissolution accelerator.

In some embodiments, the first functional component is selected from one or more of low molecular weight alcohol compounds, low molecular weight carbohydrate compounds and heparin.

Herein, the alcohol compound includes alcohol and its derivatives.

Herein, carbohydrate compounds include sugar and its derivatives.

The "low molecular weight" in low-molecular-weight alcohol compounds and low-molecular-weight sugar compounds can be independently less than 5000Da, further less than 4000Da, further less than 2000Da, further less than 1500Da, and further less than 1500Da. 1000Da, further can be less than 500Da and so on.

In some embodiments, the low molecular weight alcohol compound is mannitol.

In some embodiments, low molecular weight carbohydrate compounds include: glucose, fructose, α-D-mannose, mannose, inosose; sucrose, lactose, trehalose, maltose; dextran, raffinose, inulin, dextran , maltodextrin, soluble starch sugar, maltopolysaccharide, cyclodextrin; sucrose octasulfate; and derivatives of any of the foregoing.

Soluble starch sugars refer to degradation products derived from starch and are soluble in water.

The cyclodextrins herein may be α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin.

In some embodiments, based on 100 parts by weight of the pharmaceutical composition, the parts by weight of the first functional component are 0.05 to 5 parts, further 0.1 to 5 parts, further 0.5 to 5 parts, and further 1 to 5 parts by weight. 5 servings. The parts by weight of the first functional component are for example 0.05, 0.1, 0.2, 0.4, 0.5, 0.6, 0.8, 1, 1.2, 1.4, 1.5, 1.6, 1.8, 2, 2.2, 2.4, 2.5, 2.6, 2.8, 3, 3.2, 3.4, 3.5, 3.6, 3.8, 4, 4.2, 4.5, 4.6, 4.8, 5 parts by weight.

aqueous solvent

The aqueous solvent is an essential component of the pharmaceutical composition of the first aspect, so as to achieve sufficient dispersion among the various components. Aqueous solvents are used to dissolve the components so that they can be formulated into a mixture that can be poured into molds.

The term "aqueous solvent" as used herein refers to a solvent or solution containing water, which may be a single solvent composed of pure water, or a mixed solvent formed by miscibility of water and other solvents. Solvents that can be miscible with water include, but are not limited to: alcoholic solvents (such as methanol, ethanol, propanol, isopropanol, polyethylene glycol, etc.). Salt components are also allowed in aqueous solvents.

In some embodiments, the aqueous solvent is water. Such as distilled water, purified water, filtered water, deionized water, etc.

In some embodiments, the aqueous solvent is a buffer component.

The term "buffer component," as used herein, also referred to herein as "buffer solution," refers to an aqueous solution or composition that resists changes in pH when an acid or base is added to the solution or composition. This resistance to pH changes is due to the buffering properties of such liquids. Therefore, a solution or composition exhibiting buffering activity is called a buffer or buffer solution. Buffers generally do not have an unlimited ability to maintain the pH of a solution or composition. Instead, they are generally capable of maintaining a pH within a specific range, for example pH6-pH8. Generally, buffers are capable of maintaining a pH within one logarithm above and the next logarithm of their pKa (see, eg, Mohan, Buffers, A guide for the preparation and use of buffers in biological systems, CALBIOCHEM, 1999). Buffers and buffer solutions are generally prepared from buffer salts or non-ionic buffer components such as TRIS and HEPES, and may also be selected from weak acids, salts of weak acids, or a combination of both. The buffer component in i) that can be used in the method of the present application can preferably be selected from 0.5 The concentration of Tris-HCl from mmol/L to 500mmol/L can also be selected from 1mmol/L, 5mmol/L, 10mmol/L, 50mmol/L, 100mmol/L, 200mmol/L, 300mmol/L and 400mmol/L. The buffer component in the present application can preferably be selected from one or more of a) citric acid, acetic acid, phosphoric acid, tartaric acid, malic acid, carbonic acid, barbituric acid, or b) the acid group of a, or c) the acid group of a Acidic acid (usually with one or two hydrogen ions, such as hydrogen phosphate, dihydrogen phosphate), or one or more components selected from the group consisting of a), b), and c). The buffer component is citric acid of 1mmol/L-5mmol/L, and the concentration of examples such as 2mmol/L, 3mmol/L, 4mmol/L can also be selected.

In some embodiments, the aqueous solvent is water or an aqueous solution of a pH buffer. "Aqueous solution of pH buffering agent" refers to an aqueous solution formed by dissolving a pH buffering agent in water.

In some embodiments, the pH of the aqueous solution of the pH buffer is 4-9; further, it may be 6.2-7.6.

In some embodiments, the pH fluctuation range of the aqueous solution of the pH buffer is ±2, further ±1, further ±0.5.

In some embodiments, the pH buffering agent is selected from one or more of sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid and sodium hydroxide.

In some embodiments, the "aqueous solution of pH buffer" is a PBS solution.

In some embodiments, based on 100 parts by weight of the pharmaceutical composition, the parts by weight of the aqueous solvent are 40-90 parts, further such as 50-90 parts. The parts by weight of the aqueous solvent are for example 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 60, 65, 70, 75, 80, 85, 90 and other parts by weight. Based on 100 parts by weight of the pharmaceutical composition, the parts by weight of the aqueous solvent can also be selected from any of the following ranges: 40-60 parts, 40-50 parts, 60-90 parts, 70-90 parts, 80-90 parts, etc. .

In some embodiments, the aqueous solvent is physiological saline.

Organic solvents

In this application, the organic solvent is optional, that is, dispensable.

In some embodiments, the pharmaceutical composition of the first aspect does not contain organic solvents.

In some preferred embodiments of the present application, the pharmaceutical composition of the first aspect contains an organic solvent.

Organic solvents can solubilize poorly soluble components. Some organic solvents can also play a role in promoting penetration. In the process of preparing microneedles, the drying step involved will cause a part of the solvent (aqueous solvent, organic solvent or a combination thereof) to volatilize. Therefore, compared with the pharmaceutical composition of the first aspect of the application, the prepared pharmaceutical microneedles In needles, microneedle preparations, and microneedles in microneedle drug delivery systems, the content of aqueous solvents, organic solvents, or combinations thereof may be reduced.

In some embodiments, the organic solvent contains one or more of propylene glycol, dimethyl sulfoxide, and ethanol.

In some embodiments, based on 100 parts by weight of the pharmaceutical composition, the parts by weight of the organic solvent is 0.05 to 5 parts, further 0.1 to 5 parts, further 0.5 to 5 parts, and further 1 to 5 parts . The parts by weight of the organic solvent are for example 0.05, 0.1, 0.2, 0.4, 0.5, 0.6, 0.8, 1, 1.2, 1.4, 1.5, 1.6, 1.8, 2, 2.2, 2.4, 2.5, 2.6, 2.8, 3, 3.2, 3.4, 3.5, 3.6, 3.8, 4, 4.2, 4.5, 4.6, 4.8, 5 parts by weight.

Solubilizers

In this application, the solubilizing agent is optional, that is, dispensable.

In some embodiments, the pharmaceutical composition of the first aspect does not contain a solubilizing agent.

In some preferred embodiments of the present application, the pharmaceutical composition of the first aspect contains a solubilizer.

In some embodiments, the solubilizer is selected from one or more of alcohol solubilizers, cyclodextrin solubilizers and surfactants (referred to as second surfactants).

In some embodiments, alcohol solubilizers include, but are not limited to, methanol, propylene glycol, and small molecule polyethylene glycol. Small molecule polyethylene glycol refers to polyethylene glycol with a molecular weight not exceeding 1000 Da, such as PEG200, PEG300, PEG400, PEG500, PEG550, PEG600, PEG650, PEG700, PEG750, PEG800, PEG900, etc.

In some embodiments, cyclodextrin-based solubilizers include, but are not limited to, hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin.

In some embodiments, the second surfactant includes, but is not limited to, Tween 80 and polysorbate.

In some embodiments, based on 100 parts by weight of the pharmaceutical composition, the parts by weight of the solubilizer are 0.05 to 5 parts, further 0.1 to 5 parts, further 0.5 to 5 parts, and further 1 to 5 parts . The parts by weight of the solubilizing agent are for example 0.05, 0.1, 0.2, 0.4, 0.5, 0.6, 0.8, 1, 1.2, 1.4, 1.5, 1.6, 1.8, 2, 2.2, 2.4, 2.5, 2.6, 2.8, 3, 3.2, 3.4, 3.5, 3.6, 3.8, 4, 4.2, 4.5, 4.6, 4.8, 5 parts by weight.

antibacterial agent

In this application, the bacteriostatic agent is optional, that is, dispensable.

In some embodiments, the pharmaceutical composition of the first aspect does not contain a bacteriostatic agent.

In some preferred embodiments of the present application, the pharmaceutical composition of the first aspect contains a bacteriostatic agent.

The addition of bacteriostatic agents can avoid bacterial infection, which is more beneficial to achieve better drug/pharmaceutical administration.

In some embodiments, the antibacterial agent is selected from quaternary ammonium salt antibacterial agents, alcohol antibacterial agents, ester antibacterial agents, acid antibacterial agents and One or more of phenolic bacteriostatic agents.

In some embodiments, quaternary ammonium salt bacteriostatic agents include, but are not limited to, benzalkonium chloride and benzalkonium bromide.

In some embodiments, alcohol bacteriostatic agents include, but are not limited to, benzyl alcohol and chlorobutanol.

In some embodiments, ester bacteriostatic agents include, but are not limited to, parabens.

In some embodiments, acid bacteriostatic agents include, but are not limited to, sorbic acid.

In some embodiments, phenolic bacteriostatic agents include, but are not limited to, phenol and cresol.

In some embodiments, the bacteriostatic agent is a cationic surfactant. In some embodiments, the bacteriostatic agent contains one or more cationic surfactants.

In some embodiments, the cationic surfactants are chitosan derivatives, polylysine derivatives, and the like.

In some embodiments, based on 100 parts by weight of the pharmaceutical composition, the parts by weight of the antibacterial agent are 0.001 to 1 part, further 0.01 to 1 part, further 0.05 to 1 part, and further 0.1 to 1 part part, further 0.2 to 1 part. The parts by weight of the antibacterial agent are, for example, 0.01, 0.02, 0.04, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 part by weight and the like.

suspending agent

In this application, the suspending agent is optional, that is, dispensable.

In some embodiments, the pharmaceutical composition of the first aspect does not contain suspending agents.

In some preferred embodiments of the present application, the pharmaceutical composition of the first aspect contains a suspending agent.

The suspending agent can avoid or slow down or reduce the sedimentation of particles by adjusting the viscosity of the system, so as to better disperse and absorb the dissolved particles.

In some embodiments, the suspending agent is selected from at least one of low molecular weight suspending agents and high molecular weight suspending agents.

In some embodiments, the weight average molecular weight of the low molecular weight suspending agent is ≤ 1000 Da. In some embodiments, the weight average molecular weight of the polymer suspending agent is greater than 1000Da.

In some embodiments, low molecular weight suspending agents include, but are not limited to, one or more of glycerin and syrups. Low molecular weight suspending agent means that the molecular weight is not more than 1000Da, preferably less than 800Da, more preferably less than 500Da, even more preferably less than 400Da.

In some preferred examples, the suspending agent is a macromolecular hydrophilic colloid substance, which is used to increase the viscosity of the dispersion medium, or adsorb on the surface of the particles to form a protective barrier, prevent or reduce the attraction or flocculation between the particles, and maintain the particles in a relatively uniform state. dispersed state.

In some embodiments, polymer suspending agents include but are not limited to cellulose suspending agents (such as methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose), carbomer, povidone , dextran, sodium alginate, agar and starch slurry in one or more. The molecular weight of the polymer suspending agent is greater than 1000Da, more preferably greater than 2000Da, further preferably greater than 5000Da.

Starch slurry, also known as starch paste, refers to the gelatinization of starch.

In some embodiments, based on 100 parts by weight of the pharmaceutical composition, the parts by weight of the suspending agent are 0.01-10 parts, further 0.1-10 parts, further 0.5-10 parts, and further 1-10 parts share. The parts by weight of the suspending agent are, for example, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 parts by weight and the like.

The Nth auxiliary material

In this application, the Nth auxiliary material is optional, that is, it is dispensable.

In some embodiments, the pharmaceutical composition of the first aspect does not contain the Nth excipient.

In some preferred embodiments of the present application, the pharmaceutical composition of the first aspect contains the Nth excipient.

The Nth auxiliary material is different from any of the above-mentioned ingredients (first active ingredient, penetration-promoting ingredient, polymer substrate ingredient, first functional ingredient, aqueous solvent, organic solvent, solubilizer, bacteriostat, suspending agent) Pharmaceutical excipients are pharmaceutically acceptable excipients.

In some embodiments, the Nth auxiliary material is selected from one or more of the following group: pH adjuster, plasticizer, magnesium agent and zinc agent.

In some embodiments, the pharmaceutical composition includes a pH adjusting agent.

In some embodiments, the pH adjuster can adjust the pH value of the mixture composed of the pharmaceutical composition to 4-9; further, it can be 6.2-7.6.

In some embodiments, the pH adjuster includes one or more of an acid and a base. The acid may be one or more of organic acids and inorganic acids. The base may be one or more of organic bases or inorganic bases. In some embodiments, the acid includes one or more of hydrochloric acid, citric acid, acetic acid, phosphoric acid, tartaric acid, malic acid, carbonic acid, barbituric acid, and the like. In some embodiments, the alkali includes one or more of sodium hydroxide, potassium hydroxide, ammonia water and the like.

In some embodiments, the pH regulator includes one or more of sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid and sodium hydroxide.

In some embodiments, the pH adjuster may include one or more of the acids and bases in the aforementioned buffer solution.

In some embodiments, based on 100 parts by weight of the pharmaceutical composition, the parts by weight of the pH regulator can be 0-5 parts by weight. Parts, further can be 0.1-5 parts, further can be 0.5-5 parts, non-limiting examples such as 0, 0.01, 0.1, 0.5, 1, 2, 3, 4, 5 parts by weight and other parts by weight. Also, for example, 0 to 1 part, 0.1 to 1 part, 0.5 to 1 part, 0 to 2 parts, 0.1 to 2 parts, 0.5 to 2 parts, etc.

In some embodiments, based on 100 parts by weight of the pharmaceutical composition, the number of parts by weight of the Nth auxiliary material is 0.01 to 10 parts, further can be 0.1 to 10 parts, further can be 0.5 to 10 parts, and can further be 1 to 10 servings. The parts by weight of the Nth auxiliary material are, for example, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 parts by weight and the like.

In some embodiments, the plasticizer is selected from one or more of polyethylene glycol, citrate and glycerin, and the citrate includes triethyl citrate, tributyl citrate and sebacic acid Dibutyl ester.

In some embodiments, the magnesium agent is selected from one or more of magnesium oxide, magnesium citrate, magnesium sulfate, magnesium orotate, magnesium lactate, magnesium chloride and magnesium acetate.

In some embodiments, the zinc agent is selected from one or more of zinc chloride, zinc acetate, zinc phosphate, zinc oxalate and zinc citrate.

technical effect

The microneedle preparation prepared according to the pharmaceutical composition of the first aspect has excellent puncture ability and dissolution performance, and can flexibly regulate the appropriate release time according to the efficacy requirements of the drug. Taking the microneedle patch as one of the embodiments as an example, after application, the puncture ability can reach 95% or higher (most can basically reach 100%), and the microneedle can dissolve within 10-240min, which shows that the patch dissolves The time can flexibly choose the appropriate release time according to the demand of drug efficacy.

Compared with injection preparations, the microneedle transdermal patch provided by the application prepared according to the pharmaceutical composition of the first aspect can achieve a substantially equivalent maximum blood drug concentration, and the time to reach the maximum blood drug concentration can be effectively delayed, and can be Maintain the maximum concentration continuously for 4-8 hours, and then slowly decrease to achieve the effect of sustained drug release for a long time. In addition, the microneedle transdermal patch provided by the present application can effectively deliver drugs for the prevention and/or treatment of osteoporosis or related bone disorders (such as parathyroid hormone-related peptides, parathyroid hormone analogues, etc., further such as A Baparatide, etc.), can effectively increase bone mineral density in subjects with osteoporosis.

Synergistic relationship between different components

In some embodiments, the ratio by weight of the first active ingredient to the penetration-promoting ingredient is 1:(0.001-5), further 1:(0.01-5), further 1:(0.1-5), and more Further, it is 1:(0.5-5), and further it is 1:(1-5).

In some embodiments, the ratio by weight of the first active component to the polymer substrate component is 1:(1-50), further (2-30):100, and further (5-30):100 . Based on 1 part by weight of the first active component, the parts by weight of the penetration-promoting component are, for example, 0.01, 0.02, 0.05, 0.1, 0.2, 0.4, 0.5, 0.8, 1, 1.5, 2, 2.5, 3, 3.5, 4 , 4.5, 5 and other parts by weight.

In some embodiments, the ratio by weight of the penetration-promoting component to the polymer substrate component is (0.01-30):100, further (0.1-30):100, and further (0.5-30):100, Furthermore, it is (1-30): 100, it is still further (2-30): 100, and it is still further (5-30): 100. Based on 100 parts by weight of the polymer substrate component, the weight percentage of the penetration-promoting component is, for example, 0.01, 0.02, 0.05, 0.1, 0.2, 0.4, 0.5, 0.8, 1, 1.5, 2, 2.5, 3, 3.5, 4 , 4.5, 5, 6, 7, 8, 9, 10, 12, 14, 15, 16, 18, 20, 22, 24, 25, 26, 28, 30 parts by weight.

In some embodiments, the ratio by weight of the first active ingredient to the first functional ingredient is 1:(0.001-5), further 1:(0.01-5), and further 1:(0.1-5), Still further, it is 1:(0.5-5), and still further, it is 1:(1-5). Taking the first active component as 1 part by weight, the parts by weight of the first functional component are, for example, 0.001, 0.01, 0.02, 0.05, 0.1, 0.2, 0.4, 0.5, 0.8, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5 parts by weight.

In some embodiments, the weight-number ratio of the first active component, the penetration-promoting component, the polymer substrate component and the first functional component is 1:(0.001-5):(1-50):(0.001-5) , further 1:(0.01～5):(1～50):(0.01～5), further 1:(0.1～5):(1～50):(0.1～5), further 1 :(0.5～5):(2～50):(0.5～5), and further 1:(1～5):(5～50):(1～5). Examples of the parts by weight of the penetration-promoting component, the polymer substrate component and the first functional component include but are not limited to those described above.

Some non-limiting examples.

In some embodiments, the pharmaceutical composition satisfies any one or more of the following characteristics:

The penetration-promoting component is selected from one or more of the following groups: surfactants, dimethyl sulfoxide and its analogues, azone compounds, pyrrolone derivatives, alcohol compounds, fatty acid compounds and penetration-promoting peptide;

The polymer substrate component is one or more of polyglycolic acid, polyvinylpyrrolidone, macromolecular sugars and macromolecular sugar derivatives (the type of the polymer substrate can also be as described in any of the preceding embodiments. definition);

The molecular weight of the polymer substrate component is 0.5 to 2 million Daltons (the molecular weight of the polymer substrate can also be defined as in any of the aforementioned embodiments);

The first functional component is selected from one or more of low molecular weight alcohol compounds, low molecular weight carbohydrate compounds and heparin; wherein, the low molecular weight alcohol compound is mannitol; the low molecular weight carbohydrate compounds include Glucose, fructose, aD-mannopyranose, mannose, inosose, sucrose, lactose, trehalose, maltose, dextran, raffinose, inulin, dextran, maltodextrin, soluble starch sugar, maltopolysaccharide, cyclic Dextrin, sucrose octasulfate, and derivatives of any of the foregoing;

The aqueous solvent is selected from water or an aqueous solution of a pH buffer; the pH of the aqueous solution of the pH buffer is 4 to 9; optionally, the pH buffer is selected from sodium dihydrogen phosphate, potassium dihydrogen phosphate, One or more of disodium hydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid and sodium hydroxide;

The organic solvent contains one or more of propylene glycol, dimethyl sulfoxide and ethanol.

In some embodiments, the polymer substrate component is a combination of polyvinylpyrrolidone and macromolecular sugar or its derivatives, and the respective molecular weights can be selected from any suitable molecular weight herein. Further, the macromolecular sugar or its derivatives can be selected from any suitable type mentioned above. In some embodiments, the macromolecular sugar or derivative thereof is dextran. At this time, the two macromolecular components cooperate with each other to provide better puncture performance and solubility for the microneedle preparation, and the macromolecular sugar or its derivatives can also play a role in protecting the active pharmaceutical ingredient (API); in addition, it can Provide better mechanical strength properties for microneedle preparations. Further, more favorable pharmacokinetics and more effective delivery of the first active ingredient in the present application can also be provided.

In some embodiments, the polymer substrate component is a combination of polyvinylpyrrolidone and dextran, and the microneedle preparation prepared based on this has a faster dissolution time of the microneedle and a quicker onset of action of the drug; the dextran can play a protective role. The role of the pharmaceutical ingredient (API); in addition, the mechanical strength of the formulation is high. See the Examples section below for the Examples. When the polymer base material is a combination of polyvinylpyrrolidone and dextran, a simple formulation can also be used to achieve better puncture performance and dissolution performance, thereby providing suitable pharmacokinetics and effectively realizing the Effective delivery of the first active ingredient results in an increase in the subject's bone density, BMD. See the Examples section below.

By controlling the proportion of each component in the pharmaceutical composition, including the polymer substrate component, to have a certain content ratio, it is beneficial to provide a more appropriate drug loading, thereby providing more appropriate pharmacokinetics and more effective drug delivery. Some non-limiting examples of this aspect are provided below and in the Examples section of this application.

By controlling the molecular weight of polyvinylpyrrolidone and macromolecular sugar or its derivatives (such as dextran), the synergistic effect of the two can provide better puncture ability and solubility of microneedle preparations, so as to better provide Pharmacokinetics for better drug delivery. Some non-limiting examples of this aspect are provided below and in the Examples section of this application.

In some embodiments, the pharmaceutical composition includes the following components in parts by weight: 0.1-18 parts of the first active ingredient, 5-40 parts of polyvinylpyrrolidone, and 0.5-25 parts of the macromolecule Sugar or its derivatives and 40-90 parts of aqueous solvent. Further, the pharmaceutical composition is composed of the above components, that is, in parts by weight, the pharmaceutical composition is composed of the following components: 0.1-18 parts of the first active ingredient, 5-40 parts of poly Vinylpyrrolidone, 0.5-25 parts of the macromolecule sugar or its derivatives and 40-90 parts of aqueous solvent. Further, based on any suitable embodiment described above, the total parts by weight of the pharmaceutical composition is 100 parts. The macromolecular sugar or its derivatives can also be as defined in any of the foregoing embodiments, some non-limiting examples include hyaluronic acid or its salts, cellulose or its derivatives, dextran or its derivatives, and the like. The types and parts by weight of the first active ingredient and the aqueous solvent may be defined independently or in combination with each other as defined in the above embodiments. In some of these embodiments, the aqueous solvent is water or physiological saline, further, the aqueous solvent may be water. In some embodiments, polyvinylpyrrolidone can correspond to the aforementioned first polymer, and macromolecule sugar or its derivatives can correspond to the aforementioned second polymer; the types, parts by weight, and weight ratio of the first polymer and the second polymer Any suitable selection may be further made within the aforementioned range. In some embodiments, the macromolecular sugar or derivative thereof is dextran.

In some embodiments, in parts by weight, the pharmaceutical composition includes the following components: 0.1-18 parts of the first active ingredient, 1-50 parts of the polymer substrate component and 40-90 parts Parts of the aqueous solvent; further, the total parts by weight of the pharmaceutical composition is 100 parts. In some embodiments, based on 100 parts by total weight of the pharmaceutical composition, the pharmaceutical composition is composed of the following components by weight: 0.1-18 parts by weight of the first active ingredient, 1-50 parts of the polymer substrate component and 40-90 parts of the aqueous solvent. The types and parts by weight of the first active component, the polymer substrate component and the aqueous solvent may be as defined in the above embodiments independently or in combination. In some of these embodiments, the aqueous solvent is water.

In some embodiments, the pharmaceutical composition includes the following components in parts by weight: 0.1-18 parts of the first active ingredient, 5-25 parts of polyvinylpyrrolidone, 0.5-25 parts of the Macromolecular sugar or its derivatives and 40-90 parts of the aqueous solvent; further, the total weight parts of the pharmaceutical composition is 100 parts. In some embodiments, based on 100 parts by total weight of the pharmaceutical composition, the pharmaceutical composition is composed of the following components by weight: 0.1-18 parts by weight of the first active ingredient, 5-25 parts of polyvinylpyrrolidone, 0.5-25 parts of the macromolecule sugar or its derivatives and 40-90 parts of the aqueous solvent. The macromolecular sugar or its derivatives can also be as defined in any of the foregoing embodiments, some non-limiting examples include hyaluronic acid or its salts, cellulose or its derivatives, dextran or its derivatives, and the like. The types and parts by weight of the first active ingredient and the aqueous solvent may be defined independently or in combination with each other as defined in the above embodiments. In some of these embodiments, the aqueous solvent is water or physiological saline, further, the aqueous solvent may be water. In some embodiments, polyvinylpyrrolidone can correspond to the aforementioned first polymer, and macromolecule sugar or its derivatives can correspond to the aforementioned second polymer; the types, parts by weight, and weight ratio of the first polymer and the second polymer Any suitable selection may be further made within the aforementioned range. In some embodiments, the macromolecular sugar or derivative thereof is dextran.

In some embodiments, the pharmaceutical composition includes the following components in parts by weight: 0.1-18 parts of the first active ingredient, 5-25 parts of polyvinylpyrrolidone, 0.5-20 parts of the Macromolecular sugar or its derivatives and 40-90 parts of the aqueous solvent; further, the total weight parts of the pharmaceutical composition is 100 parts. In some embodiments, based on 100 parts by weight of the pharmaceutical composition, the pharmaceutical composition is composed of the following parts by weight: 0.1-18 parts by weight of the first active ingredient, 5-40 parts of polyvinylpyrrolidone, 0.5-20 parts of the macromolecular sugar or its derivatives and 40-90 parts of the aqueous solvent.

In some embodiments, the pharmaceutical composition includes the following components in parts by weight: 0.1-15 parts of the first active ingredient, 5-25 parts of polyvinylpyrrolidone, 0.5-20 parts of the Macromolecular sugar or its derivatives and 40-90 parts of the aqueous solvent; further, the total weight parts of the pharmaceutical composition is 100 parts. In some embodiments, based on 100 parts by total weight of the pharmaceutical composition, the pharmaceutical composition is composed of the following components by weight: 0.1-15 parts by weight of the first active ingredient, 5-40 parts of polyvinylpyrrolidone, 0.5-20 parts of the macromolecular sugar or its derivatives and 40-90 parts of the aqueous solvent.

In some embodiments, based on any suitable embodiment described above, the sum of parts by weight of polyvinylpyrrolidone and the macromolecular sugar or its derivatives is 10-50 parts.

In some embodiments, based on any suitable embodiment described above, the macromolecular sugar or its derivative is dextran or its derivative.

In some embodiments, based on any suitable embodiment described above, the macromolecular sugar or derivative thereof is dextran.

In some embodiments, based on any suitable embodiment described above, the first active ingredient is parathyroid hormone-related peptide, and further, the first active ingredient can be abaloparatide, teriparatide, and abalatide One or more of them, further, the first active ingredient can be abaloparatide.

In some embodiments, based on any suitable embodiment above, the aqueous solvent is water, physiological saline or PBS buffer, further, the aqueous solvent can be water or physiological saline, further, the aqueous solvent is water.

In some embodiments, based on any suitable embodiment described above, the weight average molecular weight of the polyvinylpyrrolidone is 3 to 1.5 million Daltons; further optionally, the weight average molecular weight of the polyvinylpyrrolidone is 4 to 1.5 million Daltons. 1.5 million Daltons; further optionally, the weight average molecular weight of the polyvinylpyrrolidone is 250-1.5 million Daltons.

In some embodiments, based on any of the above-mentioned suitable embodiments, the weight average molecular weight of the macromolecular sugar or its derivative is 10-80 kDa; further optionally, the weight average molecular weight of the macromolecular sugar or its derivative is The molecular weight is 20-70kDa.

In another aspect of the present application, in some embodiments, based on any of the foregoing suitable embodiments, a microneedle adjuvant composition is provided. Compared with the pharmaceutical composition of the first aspect of the present application, only the first active ingredient is omitted .

In some embodiments, the microneedle auxiliary material composition includes the following components: an optional penetration-promoting component, a polymer substrate component, an optional first functional component, an aqueous solvent and an optional organic solvent, and may also include One or more of the following optional components: solubilizer, bacteriostat, suspending agent and the Nth auxiliary material; the first active ingredient is a drug for preventing and/or treating osteoporosis or related bone disorders; the first The functional ingredients are protectants and/or dissolution enhancers. The microneedle auxiliary material composition can form a pharmaceutical composition with the first active ingredient in a suitable ratio, and then prepare medicinal microneedles, pharmaceutical preparations (such as microneedle preparations), microneedle drug delivery systems, etc., so as to be used for prevention and/or Or to treat osteoporosis or related bone disorders.

In another aspect of the present application, a medicinal microneedle is provided, comprising the pharmaceutical composition described in the first aspect of the present application.

In some embodiments, the medicinal microneedles are made from a mixed solution prepared from components of the pharmaceutical composition of the first aspect of the present application.

In some embodiments, the medicinal microneedles are made from the mixture prepared from the pharmaceutical composition of the first aspect of the present application.

The medicinal microneedle can be used as a local structure of a pharmaceutical preparation, a modified structure of a drug particle, or an independent drug particle.

In some embodiments, the medicinal microneedles also carry a nano drug delivery system.

The medicinal microneedles prepared by the pharmaceutical composition in this application are soluble microneedles. Under the condition of external force, the microneedle can be inserted into the skin, and the drug can be actively delivered to the skin by dissolving in the interstitial fluid. The microneedle material can be degraded and eliminated in the skin. During the dissolving process of the soluble microneedle, all the drug in the microneedle is released, which can be controlled The drug loading of microneedles enables minimally invasive application and quantitative drug delivery; the dissolution of microneedles can also solve the secondary hazards of medical waste from needles after administration.

The second aspect of the application

In the second aspect of the present application, there is provided a microneedle preparation comprising the pharmaceutical composition described in the first aspect of the present application. The microneedle preparation has better puncture ability and dissolution performance, can provide better pharmacokinetics and drug delivery for the first active ingredient, and can improve the bone density of osteoporosis patients. Refer to the description of the first aspect.

In some embodiments, the microneedle preparation is made from a mixed liquid prepared from the components of the pharmaceutical composition of the first aspect of the present application.

In some embodiments, the microneedle preparation is made of a mixture prepared from the pharmaceutical composition of the first aspect of the present application.

In some embodiments, the microneedle formulation is a microneedle patch. A microneedle preparation provided by the present application is a microneedle patch. After application, the microneedle can dissolve within 10 to 240 minutes, which indicates that the dissolution time of the patch can be selected according to the efficacy of the drug.

In some preferred embodiments the microneedles dissolve within 120 minutes.

In some embodiments, the microneedles dissolve within 30 minutes, within 60 minutes, or within 90 minutes.

Unless otherwise stated, the above dissolution time refers to the dissolution time of the body.

In some embodiments, the microneedle patch includes microneedle bodies and a base, the microneedle bodies being microprojections protruding from the base. The microneedle body is a soluble microneedle, and the base is a soluble material. The substrate in the microneedle preparation provided by the present application can be soluble, and can be peeled off from the skin after administration and dissolution. The aforementioned "soluble" means that it can disintegrate after being inserted into the skin, thereby releasing active ingredients with therapeutic effects.

"Micro" in the microprojection means that any one dimension in the radial direction (direction substantially parallel to the base) and the height direction (direction substantially perpendicular to the base) does not exceed 1 mm. Substantially parallel and substantially perpendicular allow slight angular deviations, such as ±10°, ±5°, ±4°, ±3°, ±2°, etc., of course, including but not limited to strictly parallel (no angular deviation) and strictly perpendicular (no angle deviation) situation.

In some embodiments, the radial dimension of the microprojections is (100˜600 μm)×(100˜600 μm); and/or, the height of the microprojections is 100˜1500 μm. Examples of radial dimensions are 100 μm, 150 μm, 200 μm, 250 μm, 300 μm, 350 μm, 400 μm, 450 μm, 500 μm, 550 μm, 600 μm, and the like. Height dimensions such as 100μm, 150μm, 200μm, 250μm, 300μm, 350μm, 400μm, 450μm, 500μm, 550μm, 600μm, 700μm, 800μm, 900μm, 1000μm, 1100μm, 1200μm, 1300μm, 1400μm m, 1500, etc.

In some embodiments, the shape of the micro-projection may have the following characteristics: the cross-sectional area from the base to the top gradually decreases, so as to facilitate the integral penetration of the needle body into the skin. Some non-limiting examples are cone-shaped, and the shape of the bottom is not particularly limited, as long as the needle body can penetrate the skin smoothly. The shape of the bottom of the cone can be any polygon (such as triangle, quadrangle, pentagon, hexagon, etc.), circle, ellipse, irregular shape. Non-limiting examples of cones include, but are not limited to, pyramids (polygonal in shape at the base), conical (circular in shape at the base), and the like.

In some embodiments, the number of microneedle bodies in a single microneedle preparation is multiple, preferably 25-1200, further preferably 300-1000. For example, the number of microneedles in a single microneedle preparation is 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200 , 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1100, 1200, etc.

In some embodiments, the microneedle body is an array of microprojections.

In some embodiments, the microneedle formulation also carries a nano drug delivery system.

In some embodiments, the nano drug delivery system is selected from one or more of vesicles, micelles, cells, liposomes, microcapsules, viruses and vaccines.

The third aspect of this application

In the third aspect of the present application, a microneedle drug delivery system is provided, including the aforementioned medicinal microneedles, or the microneedle preparation described in the second aspect of the present application, and also includes The nano drug delivery system of the microneedle preparation.

In some embodiments, the nano drug delivery system is selected from one or more of vesicles, micelles, cells, liposomes, microcapsules, viruses and vaccines.

In some embodiments, the nano drug delivery system carries components that have preventive and/or therapeutic effects on osteoporosis or related bone disorders ("having a preventive and/or therapeutic effect" means having a preventive effect, a therapeutic effect, or both preventive and therapeutic effects); wherein, related bone disorders include osteopenia, osteoarthritis and fractures.

The microneedle preparation and microneedle drug delivery system provided by this application can solve some defects in the administration of traditional macromolecular drug preparations, such as the inability to achieve sustained release and the risk of toxicity due to high initial concentration.

The microneedle preparation and microneedle drug delivery system provided by this application are convenient to use, easy to operate, have good permeability of active ingredients, high bioavailability of drugs, can realize precise drug delivery, and can solve patients with osteoporosis or related bone diseases Limitations of use (such as requiring a doctor's injection) and poor compliance.

Both the microneedle preparation and the microneedle drug delivery system provided in this application can be stored in a solid form, which is beneficial to the stability of the active ingredients contained therein, and does not require too strict requirements for cold chain storage and transportation.

The fourth aspect of the application

In a fourth aspect of the present application, a method for preparing a microneedle preparation is provided, comprising the following steps:

preparing a mixed solution comprising the pharmaceutical composition described in the first aspect of the present application;

Under negative pressure conditions, inject the mixed solution into a female mold with a microneedle forming cavity;

drying and demoulding to obtain the microneedle preparation.

The microneedle forming cavity may include a microneedle body forming cavity and a base forming cavity.

In some embodiments, the mixed solution is prepared by a method comprising the following steps:

mixing the polymer substrate components with the aqueous solvent to form a blank solution;

Other components of the pharmaceutical composition (such as the first active ingredient, the optional penetration-promoting ingredient, the optional first functional ingredient, the optional organic solvent, the optional solubilizer, can be Selected antibacterial agent, optional suspending agent, etc.) are mixed with the blank solution to form a drug-containing solution, that is, the mixture.

In some embodiments, the mass concentration of the polymer substrate component in the blank solution is 5wt%˜50wt%, further may be 5wt%˜45wt%. For example, 5wt%, 10wt%, 15wt%, 20wt%, 25wt%, 30wt%, 35wt%, 40wt%, 45wt%, 50wt%, etc.

In some embodiments, the vacuum degree of the negative pressure condition is -0.05MPa to -0.1MPa, for example -0.05MPa, -0.06MPa, -0.07MPa, -0.08MPa, -0.09MPa, -0.1MPa and so on.

In some embodiments, the drying temperature is <30°C, such as 30°C, 29°C, 28°C, 27°C, 26°C, 25°C, 24°C, 23°C, 22°C, 21°C, 20°C, 19°C , 18°C, 16°C, 15°C, etc. Non-limiting examples of the drying temperature include 10˜30° C., 15˜30° C., and the like.

In some embodiments, the drying time is 8h-24h, such as 8h, 9h, 10h, 11h, 12h, 14h, 15h, 16h, 18h, 20h, 21h, 22h, 23h, 24h, etc.

In some embodiments, the vacuum degree of the negative pressure condition is -0.05MPa to -0.1MPa; and/or, the drying temperature is <30°C; and/or, the drying time is 8h-24h.

The fifth aspect of the application

In the fifth aspect of the present application, the pharmaceutical composition described in the first aspect of the present application, or the application of the medicinal microneedles described in the second aspect of the present application is provided.

In some embodiments, the application is in the preparation of pharmaceutical preparations for preventing and/or treating osteoporosis or related bone disorders.

In the fifth aspect of the present application, there is also provided the microneedle preparation described in the second aspect of the present application, or the microneedle drug delivery system described in the third aspect of the present application, or the preparation method described in the fourth aspect of the present application. The obtained microneedle preparation is used as a pharmaceutical preparation for preventing and/or treating osteoporosis or related bone diseases.

In some embodiments, the associated bone disorder includes one or more of osteopenia, osteoarthritis, and bone fracture.

In some embodiments, the pharmaceutical formulation for the prevention and/or treatment of osteoporosis or related bone disorders is a transdermal patch. Compared with transdermal injection, drug administration through the pharmaceutical microneedle, microneedle preparation or microneedle drug delivery system of the present application can improve the patient's drug compliance.

In some embodiments, the use comprises one or more of improving bone mineral density, improving trabecular bone score, and reducing fractures.

In some embodiments, the pharmaceutical formulation for the prevention and/or treatment of osteoporosis or related bone disorders is for administration on the abdomen or thigh.

In the sixth aspect of the present application, there is provided a method for preventing and/or treating osteoporosis or related bone disorders, comprising administering the microneedle preparation described in the second aspect of the present application, or the method described in the third aspect of the present application A microneedle drug delivery system, or a microneedle preparation prepared by the preparation method described in the fourth aspect of the present application.

In some embodiments, the associated bone disorder includes one or more of osteopenia, osteoarthritis, and bone fracture.

In some embodiments, the subject is a mammal.

In some embodiments, the subject has one or more of osteoporosis, osteopenia, osteoarthritis, and bone fracture.

In some embodiments, the administration is transdermal.

In some embodiments, administering the microneedle formulation includes applying a force to the microneedle formulation sufficient to drive the one or more microprojections through the stratum corneum of the subject.

In some embodiments, the site of administration is the abdomen or arm or thigh.

The application effects of the fifth aspect and the sixth aspect of the present application can also refer to the descriptions of other aspects of the present invention (including the first aspect) and the embodiments.

The microneedle preparation prepared according to the pharmaceutical composition of the first aspect has excellent puncture ability and dissolution performance, and can flexibly regulate the appropriate release time according to the efficacy requirements of the drug. Taking the microneedle patch as one of the embodiments as an example, after application, the puncture ability can reach 95% or higher (most can basically reach 100%), and the microneedle can dissolve within 10-240min, which shows that the patch dissolves The time can flexibly choose the appropriate release time according to the demand of drug efficacy.

Compared with injection preparations, the microneedle transdermal patch provided by the application prepared according to the pharmaceutical composition of the first aspect can achieve a substantially equivalent maximum blood drug concentration, and the time to reach the maximum blood drug concentration can be effectively delayed, and can be Maintain the maximum concentration continuously for 4-8 hours, and then slowly decrease to achieve the effect of sustained drug release for a long time. In addition, the microneedle transdermal patch provided by the present application can effectively deliver drugs for the prevention and/or treatment of osteoporosis or related bone disorders (such as parathyroid hormone-related peptides, parathyroid hormone analogs, etc., Further such as abaloparatide, etc.), can effectively increase the bone density of osteoporosis subjects.

In another aspect of the present application, there is also provided a pharmaceutical composition for preventing and/or treating osteoporosis or related bone disorders, the pharmaceutical composition is as defined in the first aspect of the present application. That is, there is provided a pharmaceutical composition for preventing, treating or both preventing and treating osteoporosis or related bone disorders, the pharmaceutical composition as defined in the first aspect of the present application.

Embodiments of the present application will be described in detail below in conjunction with examples. It should be understood that these examples are only used to illustrate the present application and are not intended to limit the scope of the present application. For the experimental methods that do not indicate detailed conditions in the following examples, please refer to the guidelines given in this application, or according to the experimental manual or routine conditions in this field, or according to the conditions suggested by the manufacturer, or refer to the existing conditions in this field. known experimental methods.

In the following examples, the measurement parameters related to raw material components may have slight deviations within the weighing accuracy range unless otherwise specified. Involves temperature and time parameters, allowing for acceptable deviations due to instrumental test accuracy or operational accuracy.

In the context of this application, "10,000 Daltons" can be expressed as "wDa", and "kilodaltons" can be expressed as "kDa", 1 wDa is equal to 10 kDa, which is equal to 10000 Da.

In the following examples, 10%, 9%, 8%, and 2% in 10% PVP K60, 8% PVP K90+2% Dex 2W, 9% PVP K90+2% Dex 2W, etc. refer to the relevant ingredients in the preparation of microneedles The weight percentage in the injection molding solution of the patch. "Injection molding liquid" refers to a mixed liquid that can be directly injected into the mold cavity for molding. Unless otherwise stated, the other components in the injection molding solution are water or an aqueous solution of a buffer, and the pH buffer can be selected from sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, and hydroxide One or more of sodium.

In the following examples, unless otherwise specified, the same microneedle mold is used, and the size and shape of the microneedle forming cavity are the same, and the microneedle forming cavity includes a microneedle body forming cavity and a base forming cavity.

In the following examples, the information of the equipment used is as follows.

Optical microscope: manufacturer Olympus, model SZ61TR.

Needle aid: self-made, used to force the microneedles into the stratum corneum, and the applied force is controllable.

In the following examples, PVP represents polyvinylpyrrolidone, dextran represents dextran, Dex represents dextran, and Dex 2W represents a dextran with an average molecular weight (weight average molecular weight) of 20,000 Daltons, and HA 5W represents an average molecular weight ( weight-average molecular weight) of hyaluronic acid of 50,000 Daltons. The meaning of the K value of PVP and its relationship with the molecular weight are as described above.

The preparation method of the microneedle patch is as follows:

(1) Preparation of blank solution: dissolve the polymer base material (may be polymer material PVP or sodium hyaluronate or sodium carboxymethyl cellulose, etc.) in an aqueous solvent (can be water or an aqueous solution of a pH buffer) , forming a base solution (i.e. a blank solution);

(2) Preparation of drug-containing solution: the first active ingredient (which can be abaloparatide or teriparatide or calcitonin or other osteoporosis drugs) is dissolved in the blank solution, and a protective agent ( The first functional component) and the penetration enhancer (penetration enhancer component), stirring and mixing uniformly to form a uniform solution;

(3) Take an appropriate amount of drug-containing solution (as injection molding solution), inject it into the microneedle female mold, and after vacuuming, apply it evenly, dry it and demould it, and then obtain the osteoporosis microneedle patch.

In the examples therein, the mass concentration of the polymer substrate component in the blank solution is 5%-20%.

In one of the embodiments, the vacuum and drying conditions of step (3) include: pressure of -0.05 to -0.1 MPa, temperature lower than 40°C (more specifically, temperature lower than 30°C), and time of 8 to 24 hours.

Morphological characterization: (1) Visual observation; (2) Microneedle morphology was photographed using a microscope (manufacturer Olympus, model SZ61TR). According to the morphological characterization results, the size information of a single microneedle and the size information of a microneedle array are also verified.

Puncture ability test

The puncture ability of the microneedle was detected by the isolated porcine ear skin, and the test method was as follows:

For the purchased pig ear skin, use a needle aid to insert the microneedle patch into the pigskin, then immediately pull out the patch, immediately use 0.3% trypan blue solution to soak the skin surface, and remove the staining on the skin surface after 5 minutes and wipe it clean with a non-woven cloth dipped in ethanol. Observe, count and calculate the puncture rate of the dyed pores on the surface of the skin with an optical microscope.

Puncture rate=(number of microneedles piercing pigskin/total number of microneedles in the patch)×100%.

The results show that the microneedle patch made of the pharmaceutical composition provided by the present application can achieve 100% microneedle puncture efficiency, as shown in Figure 5 for example, indicating that the microneedle has good mechanical strength and can effectively penetrate the skin.

Toughness test:

Folding is done manually, and the toughness is divided into three levels: the first level, good, easy to fold without breaking; the second level, general, there is resistance and it is not easy to fold or cannot be folded in half completely; the third level, poor, difficult to fold or fold The process breaks.

Mechanical strength test:

It can be tested with a microneedle strength tester.

The preparation of the microneedle patch of embodiment 1.PVP K60

1.1. Preparation

The preparation steps are as follows: Dissolve 5g of PVP K60 in 10g of water, dissolve at 60°C, then take the solution into a mold, vacuumize it for 30 minutes, spread it evenly, dry at room temperature and demould, and then the microneedle patch is obtained.

1.2. Testing

The morphology, toughness, mechanical strength, and puncture ability tests were carried out.

1.3. Results

According to the morphological characterization results, the microneedle size test results are basically consistent with the set parameters, refer to A and B in Figure 1. Figure 1 is a picture of the PVP K60 microneedle patch; A is the topography of the microneedle, and B is the photo of the microneedle array. The size of the microneedle conforms to the following preset range: the shape of the needle body is pyramidal, the length×width is (100-600 μm)×(100-600 μm), and the height is 100-1500 μm.

The microneedle patch has good morphology, toughness, mechanical strength and puncture ability.

Embodiment 2. Research of different base materials

2.1. The microneedle patch is prepared in the same way as in Example 1, the difference is that the polymer base material uses a combination of polyvinylpyrrolidone and dextran PVP K30/dextran instead of PVP, and the mass ratio of the two is PVP K30 /dextran=2:1. The average molecular weight of dextran is 70,000 Daltons, and the prepared microneedle patch has regular shape, good mechanical strength and good puncture ability.

2.2. The microneedle patch is prepared in the same way as in Example 1, the difference is that the polymer base material uses a combination of polyvinylpyrrolidone and dextran PVP K30/dextran instead of PVP, and the mass ratio of the two is PVP K30 /dextran=1:1, 3:2 or 2:1. The average molecular weight of dextran is 70,000 Daltons, and the prepared microneedle patch has regular shape, good mechanical strength and good puncture ability.

2.3. The microneedle patch was prepared by basically the same method as in Example 1, except that hyaluronic acid (with an average molecular weight of 800,000 Daltons) was used instead of PVP as the polymer substrate component to prepare the microneedle patch.

Example 3.

Test sample: microneedle patch 10% PVP K90 prepared by the method of Example 1. 10 parts by weight of PVP K90 are dissolved in 90 parts by weight of water to obtain an injection molding solution, which is then injected into a mold to form a microneedle patch. Test method: For purchased pig ear skin, use a needle aid to pierce the microneedle patch into the pigskin, then immediately pull out the patch, immediately soak the skin surface with 0.3% trypan blue solution, and remove the skin after 5 minutes The dyeing agent on the surface was wiped clean with a non-woven cloth dipped in ethanol, the situation of the dyed pores on the skin surface was observed with an optical microscope, and the dissolution time and puncture rate were counted and calculated.

Take a piece of pig ear skin, wipe it clean, apply the microneedle patch on the pig ear skin with a needle aid, and observe the remaining height of the needle body through a microscope at different times for evaluation.

The results can be seen in Figure 2 and Figure 3. The results show that 100% microneedle puncture efficiency can be achieved, indicating that the microneedle has good mechanical strength and can effectively penetrate the skin.

Example 4. 10% HA is used as a polymer substrate component

4.1. Preparation method

The preparation method is basically the same as in Example 1, except that hyaluronic acid (HA) is used instead of PVP as the polymer substrate component. Hyaluronic acid has a molecular weight of 50,000 Daltons. Dissolving 10 parts by weight of HA in 90 parts by weight of water to obtain an injection molding solution, which is then injected into a mold to form a microneedle patch.

4.2. Characterization and results

4.2.1.

Conduct morphology observation and characterization, and puncture ability test.

The results showed that the needle body was completely filled, but the cavity was large. The puncture ability of this microneedle patch is 100%. See Figure 7.

4.2.2. Solubility test

Model: pig ear back leather

Sample: 10% HA (5W).

Tool: needle aid

Test method: The solubility test was carried out in the same way as in Example 3, except that the observation time points were different, and the observation time points included 5 min, 10 min, 20 min, and 30 min.

Results: After 30 minutes, the microneedles were completely dissolved, as shown in Figure 8.

Example 5. Drug-loaded microneedle patch

5.1. Preparation

Dissolve 5g of PVP K30 and 5g of dextran (molecular weight: 50,000 Daltons) in 10g of water, dissolve at room temperature, then add 4g of abaloparatide, after dissolving and clarifying, take the solution into the mold, and vacuumize for 30min , coated evenly, dried at room temperature and released from the mold to obtain the microneedle drug patch. It can be recorded as PVP K30 drug-loaded microneedle patch.

5.2. Characterization

Conduct morphology observation and characterization, and puncture ability test.

Do a solubility test. The observation time points include 5min, 10min, 30min, 60min, 90min and 120min. In addition, the model uses pig ear back skin, and the humidity of the pig skin is 15% to 20%.

5.3. Results

The puncture ability test results can be seen in Fig. 9, the puncture ability of the microneedle patch is 100%.

Dissolution test results: at 60 minutes, the microneedles were completely dissolved. Refer to Figure 10 (oblique view) and Figure 11 (side view).

Embodiment 6. Pharmacokinetic test

6.1. Samples to be tested

Sample: PVP K30 drug-loaded microneedle patch (prepared in Example 5). The number of parallel samples is 2, which are respectively marked as Rat#1 and Rat#2.

6.2. Experimental method

For animal administration, rats had their abdominal hair removed in advance, and a hairless area of 3 cm × 3 cm was taken, and microneedles were inserted, fixed with medical tape, and removed after 8 hours of microneedle fixation. Blood samples were taken before administration and at 0.25, 0.5, 1, 2, 4, 8, 24, 48, and 72 hours after administration for analysis.

Needling site: the middle of the spine.

6.3. Experimental results

Please refer to Figure 13, Table 2 and Table 3 for the results of pharmacokinetic experiments. Two of the samples (Rat#1, Rat#2) reached the peak concentration 4 hours after administration, and the peak drug concentration was greater than 10ng/mL.

Table 2.

Among them, BLOQ means below the detection limit. "hr" and "h" both indicate hours.

table 3.

Among them, t _1/2 , the half-life; t _max , the peak time of the drug; C _max , the peak drug concentration, that is, the maximum blood concentration; MRT, the average residence time; AUC, the area under the zero-order moment curve; F, bioavailability ;The unit "hr" is hour.

Example 7. Preparation of different drug-loaded microneedle patches

7.1. The injection molding solution contains the first functional component and a bacteriostat

(1) Preparation of blank solution: In parts by weight, weigh 2.5 parts of PVP K30 and dissolve in 47.5 parts of purified water, stir and mix evenly to obtain a blank solution.

(2) Preparation of drug-containing solution: in parts by weight, weigh 0.05 part of abaloparatide and dissolve it in 98.4 parts of blank solution. Add 1 part of sucrose (the first functional component) and 0.1 part of phenol (bacteriostatic agent), stir and mix evenly to form a uniform drug-containing solution.

(3) Take an appropriate amount of drug-containing solution, inject it into the microneedle female mold, spread it evenly, and after vacuuming (0.1MPa), dry it at room temperature for 24 hours and demold it to obtain the osteoporosis microneedle patch.

Using the aforementioned method to investigate, the microneedle patch has good shape, toughness, mechanical strength, and puncture ability, and the time for complete dissolution of the needle body satisfies: 10-90 minutes.

7.2.

(1) Preparation of blank solution: In parts by weight, weigh 10 parts of PVP K30 and dissolve in 40 parts of purified water, stir and mix evenly to obtain a blank solution.

(2) Preparation of drug-containing solution: in parts by weight, weigh 0.05 part of abaloparatide and dissolve it in 98.4 parts of blank solution, add 1 part of sucrose and 0.1 part of phenol at the same time, stir and mix evenly to form a uniform drug-containing solution. medicine solution.

(3) Take an appropriate amount of drug-containing solution, inject it into the microneedle female mold, coat evenly, and vacuumize (0.1MPa), dry at room temperature for 24 hours and demold to obtain the osteoporosis microneedle patch.

Using the aforementioned method to investigate, the microneedle patch has good shape, toughness, mechanical strength, and puncture ability, and the time for complete dissolution of the needle body satisfies: 10-90 minutes.

7.3

(1) Preparation of blank solution: In parts by weight, weigh 25 parts of PVP K30 and dissolve in 25 parts of purified water, stir and mix evenly to obtain a blank solution.

(2) Preparation of drug-containing solution: in parts by weight, weigh 0.05 part of abaloparatide and dissolve it in 98.4 parts of blank solution, add 1 part of sucrose and 0.1 part of phenol at the same time, stir and mix evenly to form a uniform drug-containing solution. medicine solution;

(3) Take an appropriate amount of drug-containing solution, inject it into the microneedle female mold, coat evenly, and vacuumize (0.1MPa), dry at room temperature for 24 hours and demold to obtain the osteoporosis microneedle patch.

Using the aforementioned method to investigate, the microneedle patches all have good shape, toughness, mechanical strength, and puncture ability, and the time for complete dissolution of the needle body satisfies: 10-90 minutes.

7.4.

(1) Preparation of blank solution: In parts by weight, weigh 2.5 parts of PVP K30 and dissolve in 47.5 parts of purified water, stir and mix evenly to obtain a blank solution.

(2) Preparation of drug-containing solution: in parts by weight, weigh 6 parts of abaloparatide and dissolve it in 92.9 parts of blank solution, add 1 part of sucrose and 0.1 part of phenol at the same time, stir and mix evenly to form a uniform solution containing medicine solution.

(3) Take an appropriate amount of drug-containing solution, inject it into the microneedle female mold, spread it evenly, and after vacuuming (0.1MPa), dry it at room temperature for 24 hours and demold it to obtain the osteoporosis microneedle patch.

Using the aforementioned method to investigate, the microneedle patches all have good shape, toughness, mechanical strength, and puncture ability, and the time for complete dissolution of the needle body satisfies: 10-90 minutes.

7.5.

(1) Preparation of blank solution: In parts by weight, weigh 2.5 parts of PVP K30 and dissolve in 47.5 parts of purified water, stir and mix evenly to obtain a blank solution.

(2) Preparation of drug-containing solution: in parts by weight, weigh 13 parts of abaloparatide and dissolve it in 92.9 parts of blank solution, add 1 part of sucrose and 0.1 part of phenol at the same time, stir and mix evenly to form a uniform drug-containing solution medicine solution.

(3) Take an appropriate amount of drug-containing solution, inject it into the microneedle female mold, coat evenly, and vacuumize (0.1MPa), dry at room temperature for 24 hours and demold to obtain the osteoporosis microneedle patch.

Using the aforementioned method to investigate, the microneedle patches all have good shape, toughness, mechanical strength, and puncture ability, and the time for complete dissolution of the needle body satisfies: 10-90 minutes.

7.6. The polymer base material is a combination of PVP and macromolecule sugar

The drug-loaded microneedle patches were prepared by basically the same method as in Example 5, and the prepared drug-loaded microneedle patches were respectively recorded as preparations 7a-7n, and the pharmaceutical compositions 7a-7n were used, see Table 4. The injection molding liquid is composed of abaloparatide, polyvinylpyrrolidone, dextran and an aqueous solvent; the aqueous solvent of 7a-7m is water, and the aqueous solvent of 7n is PBS solution.

It was found that these microneedle patches have good morphology, toughness, mechanical strength, and puncture ability, and can be completely dissolved within 30-120 minutes. Taking the preparation 7h as an example, the needle formation of the microneedle patch is shown in Figure 4, the puncture ability test results are shown in Figure 5, and the dissolution test results at different time points are shown in Figure 6.

Table 4. The injection molding solution composition of multiple drug-loaded microneedle patches (in parts by weight)

Herein, 1wDa = 10kDa.

The microneedle preparation prepared by the combination of PVP and Dex has a faster dissolution time of the microneedle and a quicker onset of action of the drug; dextran can protect the active pharmaceutical ingredient (API); in addition, the mechanical strength of the preparation is high.

7.7. Influencing factors of pharmaceutical preparations

Microneedle preparations P1 to P12 were prepared in the same manner as in Example 5, the difference being that at least one of the weight and quantity of the polymer substrate components was different, and the amount of aqueous solvent was different. Please refer to Table 5, and the remaining parameters were the same as those in the implementation. Example 5 is the same. The injection molding solutions of formulations P1-P12 were composed of the polymer substrate components, aqueous solvent and abaloparatide shown in Table 5, respectively.

Formulation P1 omits PVP and only uses Dex as a polymer matrix component.

Formulation P2 omitted Dex and only used PVP as a polymer matrix component.

Formulation P3 omits the use of HA in place of PVP.

Formulation P4 omits the use of HA in place of Dex.

In preparations P5 and D6, the dosage of PVP was far less than that of Dex.

In formulation P7, the amount of Dex was less.

In formulation P8, the injection molding liquid is relatively thin, and the amount of aqueous solvent is relatively large.

In formulation P9, the injection molding solution is thicker, and the amount of aqueous solvent is less.

In formulation P10, the molecular weight of PVP was low.

In formulation P11, the molecular weight of Dex is relatively low.

In formulation P12, the molecular weight of Dex is relatively high.

table 5.

The morphology, mechanical strength, puncture ability, dissolution time curve and other properties were investigated respectively, see Table 6.

The results show that the comprehensive effect of the preparation combined with PVP and Dex in Example 5 is better than that of Preparations 1-12. Wherein, compared with the preparation of Example 5, the puncture ability of the preparations 1-12 in Table 5 were all worse (all had statistical significance, p<0.05, t test).

Table 6. Performance index of microneedle patch

7.8. The inventor also adjusted the content of the active ingredient abaloparatide in the above-mentioned microneedle preparations P1 to P11, and tried the following concentrations of 0.1%, 1%, 5%, and 10% relative to the weight percentage of the injection molding solution , 15%, and it was found that, for the polymer substrate components of the composition shown in Table 5, adjusting the content of the pharmaceutical active ingredient within the above range has no obvious impact on the performance of the preparation shown in Standard 6.

Example 8. Investigation of the pharmacokinetic effects of different drug-loaded microneedle preparations

Comparative Example 1. Injection preparation.

The active ingredient of the medicine is abaloparatide, the solvent is physiological saline, and the concentration is 1% (w/v).

Pharmacokinetic test results

The pharmacokinetic test was carried out in the same manner as in Example 6, and the results can be referred to Table 7.

As a result, it was found that the microneedle preparations provided by the present application (with 7b, 7f, and 7m as non-limiting examples) all exhibit good pharmacokinetic properties.

Comparative example 1 adopts injection, and the half-life is short.

Table 7. Biological experiments (the number of samples is 3)

"hr" means "hour (hour)".

Embodiment 9. Pharmacokinetic result investigation

9.1. Samples to be tested

The drug-loaded microneedle preparation of the present application (Abaloparatide microneedle transdermal patch MAP): the method of Example 5 is used to prepare the drug-loaded microneedle preparation, which is used as a transdermal patch. The injection molding solution formula is as follows: 20 μg API+ 5g PVP+1g Dex+10gH ₂ O, API is abaloparatide.

Injectable formulation SC: Abaloparatide was dissolved in physiological saline.

9.2. Pharmacokinetic test method

The method shown in Example 6 was used for pharmacokinetic testing. Male rats were used. For single administration, the dosage is 20 μg.

9.3. Experimental results

Pharmacokinetic test results can refer to Figure 14 and Table 8. Among them, the blood concentration of abaloparatide microneedle transdermal patch MAP and the single administration of injection formulation SC as a function of time curves are shown in Figure 14 .

Comparing the pharmacokinetic curves of the two preparations, it can be seen that there is a significant difference between the two curves, and the subcutaneous injection will quickly reach the maximum blood concentration and clear it faster. The administration method of the microneedle transdermal patch of the present application effectively delays the time to reach the maximum blood drug concentration, and can continuously maintain the maximum concentration for 4-8 hours, and then slowly decrease to achieve the effect of long-term sustained drug release. The maximum plasma drug concentration achieved by the two administration methods is basically the same.

Table 8. Pharmacokinetic parameters of Abaloparatide after a single administration (Abaloparatide 20 μg)

Embodiment 10. Osteoporosis treatment effect investigation

10.1. Samples to be tested

API: Abaloparatide.

Placebo: PVP and Dex composite microneedle patch without active ingredients.

Drug-loaded microneedle preparations of the present application (Abaloparatide microneedle transdermal patches MAP-60 μg, MAP-120 μg and MAP-180 μg): The method of Example 5 was used to prepare drug-loaded microneedle preparations for use as transdermal patches ; The formulations of the injection molding solution are as follows,

MAP-60μg: 60μg API+5g PVP+1g Dex+10g _H2O .

MAP-120 μg: 120 μg API + 5 g PVP + 1 g Dex + 10 g H ₂ O.

MAP-240 μg: 240 μg API + 5 g PVP + 10 g H ₂ O.

Injection preparation SC: Abaloparatide was dissolved in physiological saline, and the single administration dose was 80 μg. Recorded as SC-80μg.

10.2. Animal models

Osteoporosis model rats: Ovariectomized SD rats.

10.3. Experimental method

The model mice were given medicine every day for 6 consecutive months, and then the bone mineral density at the total hip was detected.

10.4 Experimental results

The results of bone mineral density (BMD) at the total hip at 6 months from the baseline can be seen in Figure 15, expressed as a percentage.

The results show that with the increase of the dose of the active ingredient (abaparatide) in the microneedle transdermal patch, the BMD value increases, and when the drug dose of the transdermal patch MAP reaches 240 μg, it can basically be compared with the comparison preparation SC 80 μg. The BMD results of the two groups were close, and there was no significant difference (p<0.05).

The microneedle transdermal patch provided in the present application provides an effective delivery method for preventing and/or treating osteoporosis or related bone diseases.

Regarding the above-mentioned examples and comparative examples, the inventors used the same weight of buffer solution (further PBS solution) instead of water. According to experiments, the properties of the prepared microneedle patches were similar to those of water.

Regarding the above-mentioned embodiments and comparative examples, the inventors used the same weight of normal saline instead of water. Experimental investigations showed that the various properties of the prepared microneedle patches were similar to those obtained when water was used.

The technical features of the above implementations and examples can be combined in any suitable manner. For the sake of brevity, all possible combinations of the technical features of the above implementations and examples are not described. However, as long as these techniques There is no contradiction in the combination of features, and all should be considered within the scope described in this specification.

The above embodiments only express several implementation modes of the present application, which is convenient for understanding the technical solution of the present application in detail, but should not be construed as limiting the protection scope of the present application. It should be noted that those skilled in the art can make several modifications and improvements without departing from the concept of the present application, and these all belong to the protection scope of the present application. In addition, it should be understood that after reading the above teaching content of the present application, those skilled in the art may make various changes or modifications to the present application, and the obtained equivalent forms also fall within the protection scope of the present application. It should also be understood that technical solutions obtained by those skilled in the art through logical analysis, reasoning or limited experiments on the basis of the technical solutions provided in this application are within the protection scope of the appended claims of this application. Therefore, the scope of protection of the patent application should be based on the content of the appended claims, and the description and drawings can be used to interpret the content of the claims.

Claims (20)

A pharmaceutical composition, wherein, in parts by weight, comprises the following components:

in, The first active ingredient is a drug for preventing and/or treating osteoporosis or related bone disorders; The first functional component is a protective agent, a dissolution accelerator or a combination thereof; The organic solvent is a pharmaceutically acceptable organic solvent. The pharmaceutical composition according to claim 1, wherein the total parts by weight of the pharmaceutical composition is 100 parts; Optionally, based on 100 parts by weight of the pharmaceutical composition, the parts by weight of the first active ingredient are 0.01-15 parts by weight, and the parts by weight of the aqueous solvent are 50-90 parts by weight. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition further comprises the following components:
0-5 parts of solubilizer;
0 to 1 part of antibacterial agent; 0 to 10 parts of suspending agent; Wherein, the weight part of at least one of the solubilizer, the bacteriostat and the suspending agent is not zero. The pharmaceutical composition according to any one of claims 1-3, wherein the pharmaceutical composition further comprises a pH regulator. The pharmaceutical composition according to any one of claims 1 to 4, wherein the first active ingredient is selected from one or more of the following group: bone resorption inhibitors, bone formation agents, bone morphogenesis Protein 9, activin A, semaphorin 3A, calcium, vitamin D, strontium, estrogen drugs, selective estrogen receptor modulators, pharmaceutically acceptable salts of any of the foregoing, and any of the foregoing Isofunctional derivatives, isofunctional analogs of any of the foregoing, and labels of any of the foregoing. The pharmaceutical composition according to any one of claims 1 to 5, satisfying any one or more of the following features: The dry weight ratio of the first active ingredient in the pharmaceutical composition is 0.1% to 30%; further, it can be any of the following ranges: 1% to 30%, 5% to 30%, 10% %～30%, 10%～15%, 15%～25% and 25%～30%; The penetration-promoting component is selected from one or more of the following groups: surfactants, dimethyl sulfoxide and its analogues, azone compounds, pyrrolone derivatives, alcohol compounds, fatty acid compounds and penetration-promoting peptide; The macromolecular substrate component is one or more of polyglycolic acid, polyvinylpyrrolidone, macromolecular sugar and macromolecular sugar derivatives; the weight average molecular weight of the macromolecular sugar and macromolecular sugar derivatives is independent Earth greater than 1000Da; The molecular weight of the polymer substrate component is 0.5 to 2 million Daltons; The first functional component is selected from one or more of low molecular weight alcohol compounds, low molecular weight carbohydrate compounds and heparin; wherein, the low molecular weight alcohol compound is mannitol; the low molecular weight carbohydrate compounds include Glucose, fructose, a-D-mannopyranose, mannose, inosose, sucrose, lactose, trehalose, maltose, dextran, raffinose, inulin, dextran, maltodextrin, soluble starch sugar, maltopolysaccharide, cyclic Dextrin, sucrose octasulfate, and derivatives of any of the foregoing; the weight-average molecular weights of the low-molecular-weight alcohol compounds and low-molecular-weight sugar compounds are each independently less than 5000Da; The aqueous solvent is selected from water or an aqueous solution of a pH buffer; the pH of the aqueous solution of the pH buffer is 4 to 9; the pH buffer is selected from sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate , one or more of dipotassium hydrogen phosphate, hydrochloric acid and sodium hydroxide; The organic solvent contains one or more of propylene glycol, dimethyl sulfoxide and ethanol. The pharmaceutical composition according to any one of claims 1 to 6, wherein the polymer substrate component is a combination of polyvinylpyrrolidone and macromolecular sugar or its derivatives; Optionally, in parts by weight, the pharmaceutical composition includes the following components: 0.1-18 parts of the first active ingredient, 5-40 parts of polyvinylpyrrolidone, and 0.5-25 parts of the macromolecule Sugar or its derivatives and 40 to 90 parts of the aqueous solvent; Optionally, based on 100 parts by weight of the total pharmaceutical composition, the pharmaceutical composition is composed of the following components by weight: 0.1 to 18 parts of the first active ingredient, 5 to 18 parts by weight. 40 parts of the polyvinylpyrrolidone, 0.5-25 parts of the macromolecular sugar or its derivatives and 40-90 parts of the aqueous solvent; Optionally, based on 100 parts by weight of the total pharmaceutical composition, the pharmaceutical composition is composed of the following components by weight: 0.1 to 18 parts of the first active ingredient, 5 to 18 parts by weight. 40 parts of the polyvinylpyrrolidone, 0.5-20 parts of the macromolecular sugar or its derivatives and 40-90 parts of the aqueous solvent; Optionally, based on 100 parts by weight of the total pharmaceutical composition, the pharmaceutical composition is composed of the following components by weight: 0.1 to 15 parts of the first active ingredient, 5 to 15 parts by weight. 40 parts of the polyvinylpyrrolidone, 0.5-20 parts of the macromolecular sugar or its derivatives and 40-90 parts of the aqueous solvent; Optionally, the sum of the parts by weight of the polyvinylpyrrolidone and the macromolecule sugar or its derivatives is 10-50 parts; Optionally, the macromolecular sugar or its derivative is dextran or its derivative; Optionally, the macromolecular sugar or its derivative is dextran; Optionally, the first active ingredient is parathyroid hormone-related peptide, and further optionally, the first active ingredient is one or more of abaloparatide, teriparatide and abalatide kind; Optionally, the weight average molecular weight of the polyvinylpyrrolidone is 3 to 1.5 million daltons; further optionally, the weight average molecular weight of the polyvinylpyrrolidone is 4 to 1.5 million daltons; further optionally , the weight average molecular weight of the polyvinylpyrrolidone is 250,000 to 1,500,000 Daltons; Optionally, the weight-average molecular weight of the macromolecular sugar or its derivatives is 10-80 kDa; further optionally, the weight-average molecular weight of the macromolecular sugar or its derivatives is 20-70 kDa. The pharmaceutical composition according to claim 3, wherein one or more of the following characteristics are met: The solubilizer is selected from one or more of alcohol solubilizers, cyclodextrin solubilizers and second surfactants; wherein, the alcohol solubilizers include methanol, propylene glycol and small molecule polyethylene glycol ; The cyclodextrin solubilizer includes hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin; the second surfactant includes Tween 80 and polysorbate; the small Molecular weight average molecular weight of polyethylene glycol ≤ 1000Da; The bacteriostatic agent is selected from one or more of quaternary ammonium salt bacteriostatic agents, alcohol bacteriostatic agents, ester bacteriostatic agents, acid bacteriostatic agents and phenolic bacteriostatic agents; Described suspending agent is selected from at least one in low molecular weight suspending agent and macromolecule suspending agent; Wherein, described low molecular weight suspending agent comprises one or more in glycerol and syrup, and described low molecular weight suspending agent The weight-average molecular weight of molecular weight suspending agent is less than or equal to 1000Da; Said macromolecule suspending agent comprises a combination of cellulose suspending agent, carbomer, povidone, dextran, sodium alginate, agar and starch slurry. one or more species. A microneedle preparation comprising the pharmaceutical composition according to any one of claims 1-8. The microneedle preparation according to claim 9, wherein the microneedle preparation is a microneedle patch. The microneedle preparation according to claim 9 or 10, wherein the microneedle preparation comprises a microneedle body and a base, and the microneedle body is a microprojection protruding from the base; The microneedle body is a soluble microneedle, and the base is soluble. A microneedle drug delivery system, which includes the microneedle preparation described in any one of claims 9 to 11, and also includes a nano drug delivery system connected to the microneedle preparation; Wherein, the nano drug delivery system includes one or more of vesicles, micelles, cells, liposomes, microcapsules, viruses and vaccines; The nano drug delivery system carries components that have preventive and/or therapeutic effects on osteoporosis or related bone disorders; wherein the related bone disorders include osteopenia, osteoarthritis and fractures. A method for preparing a microneedle preparation, comprising the steps of: preparing a mixed solution comprising the pharmaceutical composition according to any one of claims 1 to 8; Under negative pressure conditions, inject the mixed solution into a female mold with a microneedle forming cavity; drying and demoulding to obtain the microneedle preparation. The preparation method according to claim 13, wherein the mixed solution is prepared by a method comprising the following steps: mixing the polymer substrate components with the aqueous solvent to form a blank solution; Other ingredients in the pharmaceutical composition are mixed with the blank solution to form a drug-containing solution, that is, the mixture. The preparation method according to claim 13 or 14, satisfying one or more of the following features: The mass concentration of the polymer substrate component in the blank solution is 5wt% to 50wt%; The vacuum degree of the negative pressure condition is -0.05MPa to -0.1MPa; The drying temperature is 15-30°C; The drying time is 8h～24h. The application of the pharmaceutical composition described in any one of claims 1 to 8 in the preparation of pharmaceutical preparations for the prevention and/or treatment of osteoporosis or related bone disorders; or, The microneedle preparation described in any one of claims 9 to 11, or the microneedle drug delivery system described in claim 12, or the microneedle preparation prepared by the preparation method described in any one of claims 13 to 15 as a preventive and/or the use of pharmaceutical preparations for the treatment of osteoporosis or related bone disorders. The application according to claim 16, satisfying any one or more of the following features: Associated bone disorders include one or more of osteopenia, osteoarthritis, and fractures; The pharmaceutical preparation for preventing and/or treating osteoporosis or related bone disorders is a transdermal patch; Said use comprises one or more of improving bone mineral density, improving trabecular bone score, and reducing fractures; The pharmaceutical preparation for preventing and/or treating osteoporosis or related bone disorders is used for administration on the abdomen or thigh. A method for preventing and/or treating osteoporosis or related bone disorders, comprising administering the microneedle preparation according to any one of claims 9 to 11, or the microneedle drug delivery system according to claim 12 , or the microneedle preparation prepared by the preparation method described in any one of claims 13-15. The method according to claim 18, wherein any one or more of the following features are met: Associated bone disorders include one or more of osteopenia, osteoarthritis, and fractures; The subject is a mammal; The subject suffers from one or more of osteoporosis, osteopenia, osteoarthritis and fracture; The mode of administration is transdermal administration; Applying the microneedle formulation includes applying a force to the microneedle formulation sufficient to drive one or more of the microprojections through the stratum corneum of the subject; The application site is on the abdomen or the arm or thigh area. A pharmaceutical composition for preventing, treating or both preventing and treating osteoporosis or related bone disorders, wherein the pharmaceutical composition is as defined in any one of claims 1-8.