CN111956599A - Subcutaneous implant medicine and its composition and preparation method - Google Patents

Abstract

The invention relates to the field of medicines, in particular to a composition of a subcutaneous implant medicament, the subcutaneous implant medicament containing the composition or prepared from the composition, and a preparation method of the subcutaneous implant medicament. The composition comprises a liposome set and a matrix set, which are preserved independently of each other, wherein the liposome set comprises phospholipid and optional cholesterol; the matrix group comprises compounds with biocompatibility and biodegradability; the composition optionally further comprises a drug group, which is present in the liposome group and/or the stroma group, or is maintained separately from the liposome group and the stroma group. The subcutaneous implant prepared by the composition can stably release the medicine at a set release rate, and has strong controllability; the subcutaneously implantable medicament of the present invention can further extend the release time than the conventional hydrogel type or the tableting type.

Description

Subcutaneous implant medicine and its composition and preparation method

Technical Field

The invention relates to the field of medicines, in particular to a composition of a subcutaneous implant medicament, the subcutaneous implant medicament containing the composition or prepared from the composition, and a preparation method of the subcutaneous implant medicament.

Background

In clinic, some diseases need long-term administration control for days, months or even years, and the human body is sensitive to some drug concentrations and needs stable drug release concentration. Such as anti-cancer drugs, drugs for abstinence of drugs, cardiovascular drugs, insulin drugs, contraceptive drugs, vaccines, etc. However, conventional drug delivery systems do not meet this need, and there are many problems, such as: patients need to take medicines frequently or receive injections, and repeated disease conditions can be caused by interrupting the medicines; the blood can not be kept stable, the treatment effect is reduced, and some side effects are brought; some drugs are difficult to absorb and therefore not suitable for oral administration; the long-term and short-time interval administration is easy to miss; and the like.

Controlled release dosage forms, such as transdermal patches, nasal suppositories, anal suppositories, and the like, have been increasingly studied in response to these problems, but these dosage forms can be maintained for a short period of time, typically several hours to 5 days, and are still insufficient for conditions requiring longer dosing.

Dermal implants have also been increasingly studied in recent years, and such dosage forms are theoretically satisfactory for administration over months to years. However, the research period of the dosage form is shorter, the dosage form can be used clinically less, and the time length and stability of release are still the main pursued.

Therefore, it would be of great importance for clinical treatment to develop a novel subcutaneously implantable drug capable of releasing a sufficient amount of drug more stably for a longer period of time.

Disclosure of Invention

The present invention is directed to overcoming the above problems of the prior art and to providing a composition for subcutaneous implants, a subcutaneous implant comprising the composition or prepared from the composition, and a method for preparing the subcutaneous implant. The subcutaneous implant prepared by the composition can stably release the medicine at a set release rate, and has strong controllability; the subcutaneously implantable medicament of the present invention can further extend the release time than the conventional hydrogel type or the tableting type. The subcutaneous implant medicament of the invention is particularly suitable for sustained release of drugs which require long-term release, such as hormone drugs (e.g., testosterone drugs, estradiol drugs), insulin drugs, analgesic drugs, anticancer drugs, drug addiction treatment drugs, cardiovascular drugs, and the like.

The inventor of the present invention found that large-dose and stable drug release can be achieved by encapsulating a drug in a specific liposome and then dispersing the liposome in a matrix; and further intensive research discovers a formula combination capable of realizing a better synergistic effect.

The invention provides in a first aspect a composition for subcutaneous implantation of a medicament, the composition comprising a liposome set and a matrix set, maintained independently of each other, the liposome set comprising a phospholipid and optionally cholesterol; the matrix group comprises compounds with biocompatibility and biodegradability; the composition optionally further comprises a drug group, which is present in the liposome group and/or the stroma group, or is maintained separately from the liposome group and the stroma group.

With the liposome group and the matrix group, a better sustained release effect than that of the prior art has been achieved. To further enhance the effect, one or more of the technical features may be further preferred.

The phospholipid may be any of a variety of art-recognized modified or unmodified phospholipid compounds, and in preferred cases, the phospholipid is selected from one or more of egg yolk lecithin (EPC), sphingomyelin (ESM), soybean lecithin (Soy PC), hydrogenated soybean lecithin (HSPC), Distearoylphosphatidylcholine (DSPC), Dioleoylphosphatidylcholine (DOPC), Dimyristoylphosphatidylcholine (DMPC), palmitoylphosphatidylcholine (POPC), egg yolk phosphatidylglycerol (EPG), Distearoylphosphatidylglycerol (DSPG), Dipalmitoylphosphatidylglycerol (DPPG), Dimyristoylphosphatidylglycerol (DMPG), and phosphatidylethanolamine (mPEG-DSPE). Further preferably, the phospholipid is selected from one or more of soybean lecithin, egg yolk lecithin, distearoyl phosphatidylcholine and hydrogenated soybean lecithin.

In the present invention, the term "cholesterol" includes both cholesterol compounds represented by the formula (1) which are conventionally known in the art,

also included are various derivatives thereof; for example, the cholesterol derivative is OH, H, CH in the formula (1)_nCompounds obtained by substitution of one or more of the radicals, the substituents being chosen, for example, from-COOH, -SO₃H. -COOR, -COX (X is halogen), -CONH₂One or more of; preferably, the derivative of hyaluronic acid is-CH in p-formula (1)₃Compounds obtained by substitution of groups selected from-COOH, -SO₃H、-COOR、-COX、-CONH₂One or more of (a). Preferably, the number of substituents in one molecule of the cholesterol derivative is 3 to 15, preferably 3 to 5.

In the present invention, the liposome group may contain cholesterol, or may contain no cholesterol. Preferably, cholesterol is included.

Preferably, the content of the phospholipid is 70-100 wt% and the content of the cholesterol is 0-30 wt% based on the total weight of the phospholipid and the cholesterol; more preferably, the phospholipid is present in an amount of 75-90 wt% and the cholesterol is present in an amount of 10-25 wt%; more preferably, the phospholipid is present in an amount of 80-85 wt% and the cholesterol is present in an amount of 15-20 wt%.

The invention can achieve good slow release effect by arranging the liposome dispersed in the matrix, and can realize more stable and longer-term drug release compared with the prior art. Thus, the matrix set may be configured in a manner conventional in the art to meet the needs of such dosage forms for subcutaneous implantation of the agent.

The matrix set may be provided in a hydrogel type or a pressed sheet type.

According to a first particular embodiment of the invention, the matrix set is of the hydrogel type, the constituents of which may be those of hydrogel matrices conventionally used in the art for subcutaneous implantation of medicaments. According to further studies of the inventors of the present invention, in order to be able to perform better coordination with the liposome set of the present invention to achieve better results, one or more of the following preferred features may be further defined:

preferably, the biocompatible and biodegradable compound includes a first high molecular compound and/or a cellulose-based derivative;

preferably, the biocompatible and biodegradable compound is a mixture of a first high molecular compound and a cellulose derivative in a weight ratio of 1: (0.3-0.7), more preferably 1 (0.4-0.6);

preferably, the first polymer compound is selected from one or more of poly (lactic-co-glycolic acid) -poly (ethylene glycol) and trimethylene carbonate polymer;

preferably, the trimethylene carbonate polymer is a trimethylene carbonate-lactide copolymer and/or a trimethylene carbonate-caprolactone copolymer, more preferably, the molar ratio of trimethylene carbonate monomer to lactide monomer or caprolactone monomer is 90: 10-10: 90, and further preferably 55:45-65: 35;

preferably, the weight average molecular weight of the first polymer compound is 3000-100000;

preferably, the cellulose derivative is selected from one or more of cellulose acetate, ethyl cellulose, sodium hydroxymethyl cellulose, hypromellose, chitosan and cellulose acetate phthalate;

preferably, the cellulose derivative is cellulose acetate phthalate and hypromellose in a weight ratio of 1: (0.3-0.4).

According to a second particular embodiment of the invention, the matrix composition is of the compressed sheet type. The components of the compressed tablet matrix set may be those of compressed tablet matrices conventionally used in the art for subcutaneous implantation of pharmaceutical agents. According to further studies of the inventors of the present invention, in order to be able to perform better coordination with the liposome set of the present invention to achieve better results, one or more of the following preferred features may be further defined:

preferably, the compound having biocompatibility and biodegradability includes a second high molecular compound selected from one or more of polyethylene, polypropylene, polyethylene terephthalate, cross-linked polyester, polycarbonate, polysulfone, polystyrene, polytetrafluoroethylene, poly (1, 4-phenylene), poly (methyl methacrylate), poly (2-pentene), and polyanhydride;

preferably, the weight average molecular weight of the second polymer compound is 8000-200000;

preferably, the second high molecular compound is selected from one or more of polyanhydrides including, but not limited to, aliphatic polyanhydrides, aromatic polyanhydrides, heterocyclic polyanhydrides, polyimide anhydrides, polyamide anhydrides, and phosphorus-containing anhydrides;

more preferably, the second polymer compound is selected from one or more of poly sebacic acid glycoside (PAS), poly adipic acid dianhydride (PPA), Poly Dodecanoic Anhydride (PDA), and fumaric anhydride (PFA); more preferably, the second polymer compound is poly sebacic acid glycoside (PAS) and fumaric anhydride (PFA) in a ratio of 1: (0.3-0.5) in a weight ratio.

In the embodiment of the tablet-type, the matrix composition may optionally further comprise a film-forming compound, which is coated outside the implant to form a film, and conventional biodegradable materials may be used, or the film-forming compound may not be contained.

In the present invention, the terms "first", "second", and the like, which are added in the foregoing, do not denote any order but merely distinguish different existence environments or usage manners without being particularly specified.

In the invention, the ratio of the liposome group and the matrix group can be adjusted according to actual needs, so that the invention can realize good controllability. According to a particular embodiment, the weight ratio of the group of liposomes to the group of matrices may be 1: (1-50), more preferably 1: (1-20); more preferably 1: (4-10).

The drug group may not be included in the composition of the subcutaneously implantable medicament according to the first aspect of the present invention. It will be appreciated that although the subcutaneous implant medicament ultimately produced will necessarily contain a drug, it is not necessary to prepare the drug at the same time during the preparation of the material, and thus the composition of the present invention need not necessarily include a drug for ease of manufacture and sale.

The drug group of the present invention may contain one or more drugs, may be present in the liposome group, or in the matrix group, or both. The drug present in the liposome set is designated as a first drug and the drug present in the matrix set is designated as a second drug, which may be the same or different.

When the first drug and the second drug are the same, preferably the first drug constitutes more than 70 wt% of the total amount of the drug group, more preferably more than 85 wt%;

when the first drug and the second drug are different, the distribution of the amounts is set according to the specific clinical needs.

The specific amount of the drug is adjusted according to clinical need, and according to a specific embodiment, the weight ratio of the total weight of the phospholipid and cholesterol to the weight of the first drug is 1: (0.1-1.5), more preferably 1: (0.5-0.8).

In the present invention, it is preferable that the composition of the subcutaneously implantable medicament further comprises a penetration enhancer, and the amount of the penetration enhancer is not limited and is adjusted according to factors such as specific pharmaceutical properties, required dosage, desired release rate, and the like. According to a particular embodiment, the amount of said penetration enhancer ranges from 5 to 100 parts by weight, more preferably from 10 to 25 parts by weight, with respect to 100 parts by weight of drug.

These penetration enhancers may be present in the liposome group alone, in the matrix group alone, or in both the liposome group and the matrix group. For ease of differentiation, the penetration enhancer present in the liposome set is designated as the first penetration enhancer, and the penetration enhancer present in the matrix set is designated as the second penetration enhancer. When a penetration enhancer is present in both the liposome and matrix groups, the first penetration enhancer preferably comprises 50-90%, more preferably 70-85% of the total amount of penetration enhancer.

The first penetration enhancer and the second penetration enhancer can be respectively and independently selected from one or more of alcohols, sulfoxides, terpenes, amines, amides, fatty acids and esters, amino acids and esters thereof and phospholipid compounds; preferably, the first penetration enhancer and the second penetration enhancer are each independently selected from one or more of span 80, tween 80, span 20, oleic acid, menthol, N-methylpyrrolidone and isopropyl myristate.

The compositions of the subcutaneous implants of this invention may also contain other pharmaceutically acceptable materials or additives such as diluents, skin irritation reducing agents, carriers or vehicles, excipients, plasticizers, emollients or other additives and mixtures thereof, provided that such additives do not materially affect the basic and unique characteristics of the main ingredient.

In a second aspect, the present invention provides a subcutaneously implantable medicament comprising a matrix and liposomes dispersed in the matrix, and a drug present in the matrix and/or the liposomes; the matrix comprises or is prepared from the matrix group of the composition of the first aspect of the invention, and the liposome comprises or is prepared from the liposome group of the composition of the first aspect of the invention.

Preferably, the average particle size of the liposomes is 5nm to 5000nm, more preferably 200-600 nm. In the present invention, the average particle diameter of the particles is measured by a malvern laser particle sizer (malvern, Mastersizer 3000).

The liposome can be prepared by a method conventional in the art, such as ethanol injection, ethanol dissolution and dispersion, and the like.

In a case where the composition according to the first aspect of the present invention is contained in a subcutaneously implantable medicament, a subcutaneously implantable medicament satisfying the above-mentioned condition is within the scope of the present invention.

In another aspect, the subcutaneous implant is prepared from the composition of the first aspect of the present invention, and subcutaneous implants satisfying the above conditions are also within the scope of the present invention.

In the invention, the medicine is wrapped by the liposome, so that the slow release effect can be effectively realized, and the fluctuation of the medicine concentration can be effectively slowed down. Such subcutaneous implants are within the scope of the present invention when at least a portion of the drug is present in the liposomes.

The subcutaneous implants of the invention are particularly suitable for carrying hormonal agents such as androgenic agents (e.g., testosterone and the like and derivatives thereof) and female hormonal agents (e.g., estradiol and the like and derivatives thereof). Preferably, the medicament is selected from one or more of testosterone, methyltestosterone, dihydrotestosterone, estradiol, estrone, estriol, estradiol benzoate, estradiol valerate, ethinyl estradiol ether and gestagene; the subcutaneous implants of the invention are also suitable for carrying other drugs that require stable release over time, such as insulin, pain killers, and the like.

In a third aspect, the present invention provides a method for preparing the subcutaneously implantable medicament of the second aspect, which comprises the following steps performed on the basis of the composition of the subcutaneously implantable medicament of the first aspect of the present invention:

(1) preparing liposome: mixing the medicine, each component of the liposome group in the composition and a solvent, contacting the mixed liquid with a buffer solution to obtain a hydration liquid, and homogenizing, filming and drying the hydration liquid in sequence to obtain the liposome;

(2) preparing a matrix with the matrix components of the composition;

(3) the liposomes are dispersed in the matrix during or after the preparation of the matrix.

The materials used in the method of the third aspect of the present invention are the composition of the subcutaneous implant according to the first aspect of the present invention, and therefore the selection and amount of the specific materials are described in the first aspect and will not be described herein.

In step (1), the solvent is not particularly limited, and may be one capable of dissolving the drug and most of each component of the liposome group, and preferably, the solvent is a C2-C6 alcohol, and more preferably, one or more of ethanol, n-propanol, and isopropanol.

In step (1), the amounts of the solvent and the buffer solution used are not particularly limited, because both the solvent and the buffer solution are removed in the subsequent passage through the membrane. Preferably, the weight ratio of the liquid obtained by mixing to the buffer solution is 1: (3-100), more preferably 1: (20-50).

In step (1), the buffer solution is preferably a phosphoric acid buffer solution which is conventionally known in the art.

In step (1), the contacting conditions include: stirring at 10-40 deg.C until the mixture is in a state similar to that of an aqueous solution (i.e. hydration solution).

In step (1), the homogenization may be carried out in a manner conventional in the art, for example by means of a homogenizer or by means of microfluidics.

In step (1), the pH value of the homogenized solution is preferably 4-8, more preferably 5-7.

In the step (1), the membrane used for the membrane filtration is a microporous filter membrane with the pore diameter of 0.1-10 μm. Filtering with microporous membrane to remove solvent and obtain liposome.

In step (1), the drying may be in a manner conventional in the art, preferably by spin-drying or lyophilization.

And (3) correspondingly adopting conventional preparation measures according to the condition that the matrix is of a hydrogel type or a tabletting type, and ensuring that the liposome can be fully dispersed in the matrix.

According to a particular embodiment, when the matrix is of the hydrogel type, the process of steps (2) and (3) may comprise, for example: mixing matrix components including first polymer compound and/or cellulose derivative and second medicine in organic solvent (such as N-methyl pyrrolidone) in water bath at 90 deg.C, and homogenizing to obtain matrix; the liposomes are dispersed (e.g., by agitation or sonication) in a matrix and freeze-dried to obtain a hydrogel lyophilizate.

According to another specific embodiment, when the substrate is a laminated substrate, the process of step (2) and step (3) may include, for example: dissolving matrix components including high molecular compound and second medicine in organic solvent (such as dichloromethane), and spray drying to obtain powder. The powder is mixed with liposomes and pressed into subcutaneous implants in a piston mold by a hydraulic press.

In a fourth aspect, the invention provides a subcutaneous implant prepared by the method of the third aspect.

The subcutaneously implanted medicament of the fourth aspect of the invention has the same characteristics and properties as the subcutaneously implanted medicament of the second aspect of the invention, and will not be described in detail herein.

Through the technical scheme, compared with the prior art, the invention at least has the following advantages:

(1) the subcutaneous implanted medicament prepared from the composition can realize large-dose and stable medicament release;

(2) the composition of the invention has safe components and good biocompatibility.

The subcutaneous implant medicament of the invention can be used for various indications of corresponding medicaments.

In summary, it will be appreciated that the present invention lends itself to an unknown formulation form having practical medical utility in the field of drug delivery. While the invention has been described and pointed out in detail with reference to the operating embodiments thereof, it will be understood that various changes, modifications, substitutions and omissions may be made by those skilled in the art without departing from the spirit of the invention. Accordingly, it is intended that the patent protect equivalents of those elements included within the scope of the claims.

The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.

Detailed Description

The present invention will be described in detail below by way of examples. The described embodiments of the invention are only some, but not all embodiments of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

The starting materials and reagents not specifically described in the following examples are commercially available standard substances.

The following group a examples are presented to illustrate the liposome set of the present invention and the liposomes obtained by the preparation thereof. The products obtained in the examples are marked with the same reference numerals as in the examples. In this example group, 1 part by weight means 1 mg.

Example A1

(AI) ingredients

Phospholipid: distearoyl phosphatidylcholine, 83 parts by weight;

cholesterol: 17 parts by weight of a compound of formula (1);

a first penetration enhancer: 14 parts of isopropyl myristate;

a first drug: and 70 parts of testosterone.

(AII) preparation of liposomes

Dissolving the medicine, phospholipid and cholesterol with solvent, adding phosphate buffer solution, stirring for hydration, homogenizing with homogenizer, filtering with microporous membrane (with pore diameter of 5 μm, the same below), and lyophilizing to obtain liposome; the average particle size was determined to be 486 nm.

Example A2

(AI) ingredients

Phospholipid: 85 parts by weight of distearoyl phosphatidylcholine;

cholesterol: 15 parts by weight of a compound of formula (1);

a first penetration enhancer: 5 parts by weight of isopropyl myristate;

a first drug: 50 parts of dihydrotestosterone.

(AII) preparation of liposomes

Dissolving the medicine, phospholipid and cholesterol with a solvent, adding a phosphate buffer solution, stirring for hydration, homogenizing by a homogenizer, filtering by a microporous filter membrane, and freeze-drying to obtain liposome; the average particle size was determined to be 312 nm.

Example A3

(AI) ingredients

Phospholipid: 80 parts by weight of distearoyl phosphatidylcholine;

cholesterol: 20 parts by weight of a compound of formula (1);

a first penetration enhancer: 20 parts by weight of isopropyl myristate;

a first drug: methyltestosterone, 80 parts by weight.

(AII) preparation of liposomes

Dissolving the medicine, phospholipid and cholesterol with a solvent, adding a phosphate buffer solution, stirring for hydration, homogenizing by a homogenizer, filtering by a microporous filter membrane, and freeze-drying to obtain liposome; the average particle size was found to be 556 nm.

Example A4

Reference is made to example A1, with the difference that cholesterol is not added anymore, but is replaced by phospholipids of the same weight.

Finally obtaining the liposome.

Example A5

The procedure was carried out in accordance with example 1, except that the weight ratio of the phospholipid and cholesterol was changed, specifically, the phospholipid was changed to 50 parts by weight, and the cholesterol was changed to 50 parts by weight.

Finally obtaining the liposome.

The following group B examples are provided to illustrate the subcutaneous implants of the present invention and methods of preparation thereof. The products obtained in the examples are marked with the same reference numerals as in the examples. In this example group, 1 part by weight means 2 mg. In this group of examples, for convenience of rat testing, materials with a matrix degradation period of up to 1 year or more were not selected, but those skilled in the art will appreciate that the liposomes of the present invention can be formulated with materials with longer degradation periods to achieve further longer degradation periods and increase the stability of drug release.

Example B1

This example is a compressed tablet type subcutaneous implant.

(BI) compounding

Second polymer compound (total 700 parts by weight):

poly sebacic acid glycoside (PAS): molecular weight 20000, 500 parts by weight;

fumaric Anhydride (PFA): 200 parts by weight;

a second drug: 5 parts of testosterone;

organic solvent: dichloromethane, 2000 parts by weight;

liposome: example A1 was prepared, 100 parts by weight.

(BII) preparation of compressed tablet type subcutaneous implant

And dissolving the macromolecular compound and the second medicament in an organic solvent, and spray-drying to obtain powder. The powder and liposome are mixed, pressed into 2mm thin thread, and cut into corresponding length according to required dosage, thus obtaining the tablet subcutaneous implant medicament, which can be injected into the skin by a special injector, and the operation is simple and convenient.

Examples B2-B5

Reference is made to example B1, except that the liposomes prepared in example A1 are replaced by the same weights of the liposomes prepared in examples A2 to A5, respectively. Respectively preparing subcutaneous implantation tablets.

Example B6

Reference is made to example B1, except that the poly-sebacic acid glycosides (PAS) are all replaced by the same weight of fumaric anhydride.

Finally, the subcutaneous implant is prepared.

Comparative example BD1

Reference is made to example B1 except that instead of using the liposomes prepared in example a1, the first drug of example a1 is directly dissolved in an organic solvent along with the second drug of example B1. Finally, the subcutaneous implant is prepared.

The subcutaneous implant preparation of the invention can also be prepared into a hydrogel type, and the liposome of the invention can be dispersed in a hydrogel matrix according to the preparation requirement of the technicians in the field. This is merely an example.

Example C1

This example is a gel-type subcutaneous implant.

(CI) ingredients

A first high molecular compound: trimethylene carbonate-caprolactone copolymer (monomer molar ratio 60:40, molecular weight 25000), 400 parts by weight;

cellulose derivative (total 200 parts by weight):

150 parts by weight of cellulose acetate phthalate;

50 parts of hydroxypropyl methylcellulose;

a second drug: 5 parts of testosterone;

organic solvent: 2000 parts of N-methyl pyrrolidone;

liposome: example A1 was prepared, 100 parts by weight.

(CII) preparation of gel-type subcutaneous implant

Mixing the first high molecular compound, the cellulose derivative, the second penetration enhancer and the second medicament in an organic solvent in a water bath at 90 ℃, and homogenizing to obtain the matrix. Dispersing the liposome in the matrix under the conditions of ultrasound and stirring, and freeze-drying to obtain hydrogel lyophilized product.

Comparative example CD1

Reference is made to example C1 except that instead of using the liposomes prepared in example a1, the first drug of example a1 is directly dissolved in an organic solvent along with the second drug of example C1. Finally, the subcutaneous implant is prepared.

Test example

(1) Blood stability test

Each example and comparative example were assigned to 4 SD rats, group B was administered a dose of the agent sufficient for 6 months, respectively, in terms of body weight, and directly injected with the corresponding length of the implanted agent, group C was prepared hydrogel the hydrogel lyophilizate with physiological saline, and then administered a dose of the agent sufficient for 1 month, respectively, in terms of body weight (since the hydrogel degrades faster). After several days (as shown in Table 1), blood was collected from the tail vein and serum was separated, and the blood concentration was measured by HPLC chromatography, and the results are shown in Table 1.

TABLE 1

As can be seen from Table 1, the subcutaneous implanted medicament prepared from the composition of the present invention can release the drug at a smooth rate and control the concentration at a suitable concentration for human body, while BD1 is released at a too fast rate and the drug concentration fluctuates too much, which is likely to cause side effects on human body. It can be seen from comparison with BD1 that the present invention can significantly prolong the release time and increase the stability of the release.

(2) Duration of Release Observation

For the group B tests, the implant was removed after 5 months and tested for about 12-16% remaining implant, about 15-18% remaining drug in B1-B6, and about 10% remaining drug in BD 1.

For the group C test, the hydrogel was substantially absorbed at about 30 days in group C1, and about 11% of the liposomes remained to continue to release drug for about 50 days; the hydrogel and the drug were absorbed at about 30 days in the CD1 group.

(3) Safety observation

Through observation, the subcutaneous implanted parts of the rats are quickly healed, and the phenomena of obvious allergy, red swelling and the like are not generated. The product of the invention is proved to have good biocompatibility and safety.

The preferred embodiments of the present invention have been described above in detail, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, many simple modifications can be made to the technical solution of the invention, including combinations of various technical features in any other suitable way, and these simple modifications and combinations should also be regarded as the disclosure of the invention, and all fall within the scope of the invention.

Claims (10)

1. A composition for subcutaneous implantation of a pharmaceutical agent, the composition comprising a liposome set and a matrix set maintained independently of each other, the liposome set comprising a phospholipid and optionally cholesterol; the matrix group comprises compounds with biocompatibility and biodegradability; the composition optionally further comprises a drug group, which is present in the liposome group and/or the stroma group, or is maintained separately from the liposome group and the stroma group.

2. The composition of claim 1, wherein the phospholipid is selected from one or more of egg yolk lecithin, sphingomyelin, soybean lecithin, hydrogenated soybean lecithin, distearoylphosphatidylcholine, dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine, palmitoylendoylphosphatidylcholine, egg yolk phosphatidylglycerol, distearoylphosphatidylglycerol, dipalmitoylphosphatidylglycerol, dimyristoylphosphatidylglycerol, and pelidylphosphatidylethanolamine;

preferably, the phospholipid is selected from one or more of soybean lecithin, egg yolk lecithin, distearoyl phosphatidylcholine and hydrogenated soybean lecithin;

preferably, the content of the phospholipid is 70-100 wt% and the content of the cholesterol is 0-30 wt% based on the total weight of the phospholipid and the cholesterol; more preferably, the phospholipid is present in an amount of 75-90 wt% and the cholesterol is present in an amount of 10-25 wt%.

3. The composition according to claim 1 or 2, wherein the matrix component is of hydrogel type or of pressed sheet type;

when the matrix composition is of a hydrogel type, the compound having biocompatibility and biodegradability comprises a first high molecular compound and/or a cellulose derivative, wherein the first high molecular compound is selected from one or more of polylactic-co-glycolic acid-polyethylene glycol and trimethylene carbonate polymer, and the cellulose derivative is selected from one or more of cellulose acetate, ethyl cellulose, sodium hydroxymethyl cellulose, hypromellose, chitosan and cellulose acetate phthalate; preferably, the biocompatible and biodegradable compound is a mixture of a first high molecular compound and a cellulose derivative in a weight ratio of 1: (0.3-0.7);

when the matrix assembly is a compression sheet type, the compound having biocompatibility and biodegradability includes a second high molecular compound selected from one or more of polyethylene, polypropylene, polyethylene terephthalate, cross-linked polyester, polycarbonate, polysulfone, polystyrene, polytetrafluoroethylene, poly (1, 4-phenylene), poly (methyl methacrylate), poly (2-pentene) and polyanhydride; preferably, the second polymer compound is poly sebacic acid glycoside (PAS) and fumaric anhydride (PFA) in a ratio of 1: (0.3-0.5) in a weight ratio.

4. The composition of claim 1 or 2, wherein the drug group comprises a first drug present in the liposome group and optionally a second drug present in the matrix group, the first drug and the second drug being the same or different;

preferably, when the first drug and the second drug are the same, the first drug accounts for more than 70 wt% of the total amount of the drug group;

preferably, the weight ratio of the total weight of the phospholipids and cholesterol to the first drug is 1: (0.1-1.5).

5. The composition of claim 1, wherein the weight ratio of the liposome set and the matrix set is 1: (1-50);

preferably, the composition further comprises a penetration enhancer, wherein the penetration enhancer is present in the liposome group and/or the matrix group;

preferably, the amount of the penetration enhancer is 5 to 100 parts by weight with respect to 100 parts by weight of the drug group.

6. A subcutaneously implantable medicament, which comprises a matrix and liposomes dispersed in the matrix, and a drug present in the matrix and/or the liposomes; the matrix comprises or is prepared from a matrix group in the composition of any one of claims 1-5, and the liposome comprises or is prepared from a liposome group in the composition of any one of claims 1-5.

7. The subcutaneous implant agent as in claim 6, wherein said liposome has a particle size of 5nm to 5000 nm.

8. A method for preparing the subcutaneously implantable medicament of claim 6 or 7, which comprises carrying out the following steps starting from a composition of the subcutaneously implantable medicament of any one of claims 1 to 5:

(1) preparing liposome: mixing the medicine, each component of the liposome group in the composition and a solvent, contacting the mixed liquid with a buffer solution to obtain a hydration liquid, and homogenizing, filming and drying the hydration liquid in sequence to obtain the liposome;

(2) preparing a matrix with the matrix components of the composition;

(3) the liposomes are dispersed in the matrix during or after the preparation of the matrix.

9. The method according to claim 8, wherein in step (1), the pH value of the homogenized solution is 5-7.

10. A subcutaneous implant prepared by the method of claim 8 or 9.