A semaglutide oral patch and its preparation method and application

Abstract

The present invention discloses a semaglutide oral patch and a preparation method and application thereof, belonging to the field of pharmaceutical preparations. The oral patch comprises the following ingredients: 0.3-0.8 parts of semaglutide, 0.3-0.8 parts of an absorption enhancer, 1-2 parts of a film former and 0.2-0.5 parts of a plasticizer; wherein the film former is composed of hydroxypropyl cellulose, hydroxyethyl cellulose and carboxymethyl cellulose. The oral patch of the present invention has the advantages of high drug loading, high bioavailability, excellent demoulding, mechanical properties, taste and no drug precipitation, and is used to treat type 2 diabetes.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and specifically relates to a semaglutide oral patch and a preparation method and application thereof. Background Art

[0002] Semaglutide is a human GLP-1 analog. GLP-1 is a polypeptide hormone secreted by intestinal cells. It promotes insulin secretion and inhibits glucagon secretion in a glucose concentration-dependent mechanism by binding to the GLP-1 receptor, thereby promoting glucose metabolism. Semaglutide can significantly improve blood sugar levels in patients with type 2 diabetes. At the same time, it can also delay gastric emptying and suppress appetite, inducing weight loss by reducing appetite and food intake.

[0003] There are currently two dosage forms of semaglutide on the market: semaglutide oral tablets and semaglutide injection, which are indicated as adjuncts to diet and exercise to improve blood sugar control in type 2 diabetes or adults. Although the oral tablets on the market can make up for the inconvenience of injection for patients, the bioavailability is not high, so there is still inconvenience in clinical use.

[0004] Oral film refers to a film-like preparation obtained by processing film-forming materials and drugs for oral or mucosal use. Oral film has the following advantages: 1) small size, light weight, easy to carry, store and transport; 2) accurate dosage, simple preparation process and low cost; 3) no need to take with water, just stick it on the cheek of the mouth, and can be taken anytime and anywhere; 4) no obvious foreign body sensation after taking it, the drug is delivered through the mucosa, and the drug can enter the blood system directly through the mucosa to avoid the first-pass effect; 5) it has good compliance, especially suitable for children, the elderly and patients with dysphagia with vomiting symptoms.

[0005] However, oral patches have the following defects: due to their small size and light weight, the drug loading is often small; they are soft and have certain hygroscopicity, poor demoulding performance, etc.; if the toughness is too low, they are prone to tearing when taken; the disintegration time is too short and long-term drug delivery cannot be completed. In addition, due to the different properties of drugs, for semaglutide, considering the requirements of drug loading, demoulding performance, hygroscopicity, physical properties, taste, etc., the existing oral dissolving film formula composition cannot solve the above technical problems. Therefore, the research on semaglutide oral patches still needs to be further developed and improved.

[0006] In view of this, the present invention provides a semaglutide oral patch and a preparation method thereof, which solves the defects of the prior art. Summary of the invention

[0007] In view of the prior art, the present invention provides a semaglutide oral patch and a preparation method and application thereof. The present invention provides a semaglutide oral patch having the advantages of high drug loading, excellent demoulding and mechanical properties, no drug precipitation and long disintegration time by optimizing the release agent.

[0008] To achieve the above-mentioned object of the invention, the technical solution of the present invention is as follows:

[0009] On the one hand, the present invention provides a semaglutide oral patch, which comprises the following components in parts by weight: 0.3-0.8 parts of semaglutide, 0.3-0.8 parts of absorption enhancer, 1-2 parts of film former and 0.2-0.5 parts of plasticizer; wherein the film former is composed of hydroxypropyl cellulose, hydroxyethyl cellulose and carboxymethyl cellulose.

[0010] Preferably, the semaglutide oral patch comprises the following components in parts by weight: 0.4-0.7 parts of semaglutide, 0.3-0.6 parts of absorption enhancer, 1-1.5 parts of film former and 0.2-0.3 parts of plasticizer.

[0011] More preferably, the semaglutide oral patch comprises the following ingredients in parts by weight: 0.6 parts of semaglutide, 0.5 parts of absorption enhancer, 1.3 parts of film former and 0.25 parts of plasticizer.

[0012] Preferably, the viscosity of the hydroxypropyl cellulose is 3-500 mPa.s; the viscosity of the hydroxyethyl cellulose is 70-150 mPa.s; and the viscosity of the carboxymethyl cellulose is 20-70 mPa.s.

[0013] Further preferably, the hydroxypropyl cellulose is selected from type SL, L or M.

[0014] Further preferably, the hydroxyethyl cellulose is selected from type 250LR.

[0015] Further preferably, the carboxymethyl cellulose is selected from models 7LPEP and 7LFPH.

[0016] Preferably, the weight ratio of hydroxypropyl cellulose, hydroxyethyl cellulose and carboxymethyl cellulose is 0.2-0.3:0.02-0.08:1.

[0017] More preferably, the weight ratio of hydroxypropyl cellulose, hydroxyethyl cellulose and carboxymethyl cellulose is 0.25:0.05:1.

[0018] Preferably, the mass content of semaglutide in the tablet is 15%-30%.

[0019] Further preferably, the mass content of semaglutide in the tablet is 20%-25%.

[0020] Preferably, the sum of the weight of the semaglutide, film-forming agent, absorption enhancer and plasticizer accounts for 90-100 wt % of the total weight of the oral patch.

[0021] Preferably, the plasticizer is selected from one or more of triethyl citrate, propylene glycol and glycerol.

[0022] A second aspect of the present invention relates to a method for preparing the above-mentioned oral patch, comprising the following steps:

[0023] (1) adding a film-forming agent and a plasticizer to an aqueous solution to obtain a solution 1;

[0024] (2) adding an absorption enhancer and semaglutide to solution 1 to obtain solution 2;

[0025] (3) coating solution 2 on a release film material, drying, demoulding, and cutting to obtain the product.

[0026] Preferably, the coating thickness in step (3) is 0.6-1.2 mm, such as 0.6 mm, 0.8 mm, 1.0 mm, 1.2 mm.

[0027] Preferably, the drying temperature in step (3) is 50-70°C, such as 40°C, 50°C, 55°C, 60°C, 65°C, 70°C, etc.

[0028] Preferably, the release film material in step (3) is a conventional film material in the art, such as PET film (high temperature resistant polyester film) or PP film (polypropylene film).

[0029] The third aspect of the present invention relates to the use of the above-mentioned oral patch or the oral patch prepared by the above-mentioned preparation method in the preparation of a drug for treating type II diabetes.

[0030] The beneficial effects of the present invention include:

[0031] (1) The disintegration time of the semaglutide oral patch of the present invention is more than 0.5 hours, and the drug can be administered in the oral cavity for a long time without drinking water;

[0032] (2) The present invention overcomes the problem that the conventional oral patch is easy to break after demoulding, has moderate toughness, and the prepared oral patch is easy to cut, package, store and transport;

[0033] (3) The present invention overcomes the problem of low bioavailability of semaglutide oral tablets;

[0034] (4) The semaglutide oral patch of the present invention has an excellent taste and almost no bitterness;

[0035] (5) The preparation process of the oral patch of the present invention is simple, easy to control, and suitable for industrial production.

[0036] Terms and Claims of the Present Invention:

[0037] 1. As used herein, the articles “a”, “an” and “the” include plural referents unless expressly limited to one or more referents otherwise.

[0038] 2. As used herein, numerical range: Unless otherwise expressly indicated, all ranges or ratios disclosed herein will be understood to include any and all sub-ranges or sub-ratios contained therein. For example, a range or ratio of 1 to 30 stated should be considered to be included between a minimum value of 1 and a maximum value of 30, and any sub-range or sub-ratio, integer, decimal, or sub-range or sub-ratio consisting of integers or decimals including the end points.

[0039] 3. As used herein, the terms "comprises," "including," "have," "have," "may," "contain" and variations thereof mean open-ended conjunctions or terms that do not exclude the possibility of additional compositions or structures. DETAILED DESCRIPTION

[0040] The following non-limiting examples can enable those skilled in the art to more fully understand the present invention, but do not limit the present invention in any way. The following content is only an exemplary description of the scope of the present invention, and those skilled in the art can make various changes and modifications to the invention of the present invention based on the disclosed content, and they should also fall within the scope of the present application.

[0041] The present invention is further described below by way of specific examples. The various chemical reagents used in the examples of the present invention are obtained through conventional commercial channels unless otherwise specified. Unless otherwise specified, the contents described below are all weight contents. Unless otherwise specified, it is understood that the process is carried out at room temperature.

[0042] The sources of some raw materials used in the embodiments and comparative examples are as follows:

[0043] Semaglutide was purchased from Hubei Jianxiang Biological;

[0044] SNAC was purchased from Hubei Guangao Biological;

[0045] Hydroxypropyl cellulose was purchased from Japan Soda;

[0046] Hydroxyethylcellulose was purchased from Ashland;

[0047] Carboxymethyl cellulose was purchased from Ashland;

[0048] Propylene glycol was purchased from Hunan Erkang Pharmaceutical.

[0049] Experimental Example 1:

[0050] The formulations of Examples 1-9 are shown in Table 1.

[0051] Table 1: Formulations of Examples 1-9 (in g)

[0052]

[0053]

[0054] Note: Purified water is a material not included in the final oral patch and is removed during drying; / indicates that the ingredient is not added or is not included in the final product.

[0055] Examples 1-9 were prepared according to the following method:

[0056] (1) Weigh various components according to the formula shown in Table 1;

[0057] (2) Preparation of a polymer material mixed solution: adding a film-forming agent to an aqueous solution, stirring, and continuously adding a plasticizer to obtain a polymer material mixed solution;

[0058] (3) Preparation of drug solution: adding absorption enhancer and semaglutide to the polymer material mixture and stirring to obtain a drug solution;

[0059] (5) The drug solution was evenly coated on the release film material using a coating machine, with a coating thickness of 0.8 mm. The backing material was a PET film, and the film was dried at 65° C. and demolded to obtain an oral patch.

[0060] The oral patches prepared in Examples 1-9 were tested for performance, and the testing method was as follows:

[0061] Determination of the number of fractures: Cut the oral patch into samples with a length of 10 mm and a width of 10 mm, and fold them repeatedly by hand until they break. Record the number of folds to evaluate the folding resistance of the oral patch. 1 means that it breaks after folding once; 2 means that it breaks after folding twice; 3 means that it breaks after folding ≥ 3 times. (Breakage means the appearance of cracks).

[0062] Demolding test: The oral patch is manually peeled off from the release material to examine whether it is easy to peel off, 1 means it cannot be demolded; 2 means it is difficult to demold but can be demolded; 3 means it is easy to demold.

[0063] Determination of drug precipitation: Observe with naked eyes whether there is drug crystal precipitation in the orodispersible film; 1 means that the drug has precipitated on the film surface over a large area; 2 means that the drug has precipitated on the edge of the film; 3 means that there is no drug precipitation.

[0064] Disintegration time determination: Cut the oral patch into 4 cm 2 After sizing, the disintegration time was tested using a disintegration tester.

[0065] Strength test: Referring to GB / T1040-2006 "Determination of tensile properties of plastics", the oral patch was cut into specimens with a length of 2 mm and a width of 2 mm. The tensile speed was 9 mm / min until the film broke, and the elongation at break was tested.

[0066] The performance test results are shown in Table 2.

[0067] Table 2: Performance test results of Examples 1-9

[0068] Example Number of fractures Mold release Drug precipitation Disintegration time (min) Elongation at break (%) 1 2 2 2 23 3.5 2 2 2 2 20 3.2 3 1 2 2 32 2.6 4 2 1 3 25 3.1 5 3 3 3 38 4.5 6 1 1 2 12 1.7 7 2 2 1 10 1.8 8 1 1 1 8 1.3 9 2 1 2 14 2.0

[0069] The above results show that the proportion of film-forming agents and the specific composition of film-forming agents have a significant effect on the performance of oral patches. Regarding the proportion of each component of the film-forming agent, the total score of the three properties of breaking times, demoulding properties, and drug precipitation in Examples 1-4 is 5-6 points, the performance is general, and the disintegration time and fracture elongation rate are not as good as those in Example 5. For Examples 6-9, when the total amount of film-forming agents remains unchanged, when the film-forming agents are one or two combinations, the breaking times are all lower than 3, the demoulding properties and drug precipitation are poor, the dissolution time is short, the drug administration cannot be completely achieved, and it is easy to fall off; the fracture elongation rate is poor. In Example 5 of the present invention, the film-forming agent is composed of three components: hydroxypropyl cellulose, hydroxyethyl cellulose, and carboxymethyl cellulose, and at a specific ratio, the comprehensive performance of the oral patch obtained is excellent.

[0070] At the same time, according to the composition of the components in Example 5, since purified water is a material not contained in the final oral patch and is removed during drying, the amount of water is removed in the calculation. According to the amount of the remaining components excluding water, it can be seen that the content of semaglutide in the oral patch is as high as about 22.64%, and no drug is precipitated, which solves the problem of low drug loading in existing oral patches.

[0071] At the same time, the taste test of Examples 1-9 was carried out, and the test process was as follows:

[0072] 40 volunteers aged 20-26 years old tested the samples obtained in Examples 1-9 respectively; 1 means bitter, producing an unpleasant or tolerable taste; 2 means relatively bitter or slightly bitter, relatively obvious or perceptible, with an unpleasant taste; 3 means no bitterness at all. The number of people who gave each sample a score of 3 points, 2 points, and 1 point was recorded respectively. The test results are shown in Table 3.

[0073] Table 3: Test results of oral patch taste of Examples 1-9

[0074] Example People who rated 3 People who rated 2 People who rated 1 1 20 12 8 2 15 17 8 3 23 10 7 4 16 15 9 5 37 3 0 6 6 15 19 7 9 10 21 8 5 10 25 9 8 15 17

[0075] The results showed that the use of different film-forming agents unexpectedly had a significant effect on the taste. When a combination of hydroxypropyl cellulose, hydroxyethyl cellulose and carboxymethyl cellulose was used, the prepared oral patch had an excellent taste and almost no odor.

[0076] Experimental Example 2: Pharmacokinetic Experiment

[0077] The oral patches prepared in Examples 5-9 were subjected to pharmacokinetic experiments, and semaglutide tablets were used as a reference preparation. The experimental process is as follows:

[0078] 18 rats were randomly divided into Example 5-Example 9 group and reference preparation group, 3 rats in each group, and were raised normally for one week. They were fasted but not watered for 12 hours before administration. The rats were anesthetized, and the rats in Example 5-Example 9 group were given oral patches at a dosage of 3.96 mg / kg. The oral patches adhered to the buccal mucosa of the oral cavity. The rats in the reference preparation group were given oral administration at a dosage of 4.43 mg / kg. Whole blood was collected from the limb veins at 5min, 15min, 0.5h, 0.75h, 1h, 2h, 4h, and 8h after administration, and blood collection avoided the administration site.

[0079] Plasma sample processing: 0.6 mL of whole blood was collected from the veins of the four limbs at each time point, placed in a commercial blood collection tube containing K2EDTA anticoagulant (supplier: Shanghai Aoxiang Medical Technology Co., Ltd.), placed on wet ice, and centrifuged within 30 minutes after blood collection (3000g, 4°C, centrifugation for 10 minutes) to collect plasma, transfer the plasma to a new EP tube, and store it in an environment of -90 to -60°C.

[0080] Accompanying standard curve: Accurately pipette 10 mg / mL semaglutide stock solution and dilute it with methanol-water-ammonia (1:1:0.1%, v / v / v) to prepare standard solutions with concentrations of 0.1, 0.2, 0.4, 1, 2, 4, 10, 16 and 20 μg / mL, respectively. Accurately pipette 2.5 μL of each standard solution and add it in parallel to 47.5 μL of blank rat plasma to prepare standard curve samples with semaglutide concentrations of 5, 10, 20, 50, 100, 200, 500, 800 and 1000 ng / mL, respectively, and operate according to the "Rat Plasma Sample Processing" item. The prepared samples were determined by high performance liquid chromatography. The ratio of the sample and internal standard peak areas was used as the vertical axis, the concentration (ng / mL) was used as the horizontal axis, and 1 / X 2 Regression was performed with the weight coefficient to obtain the concentration of semaglutide in rat plasma.

[0081] Data processing: All measured data were collected and processed by MassHunter software, and the data were calculated and processed using Microsoft Excel. The results are shown in Table 4.

[0082] Table 4: Drug concentrations in rat plasma at different blood collection time points

[0083]

[0084] Note: BLOQ stands for below limit of quantitation.

[0085] The above experimental results show that the oral patch prepared in Example 5 of the present invention can be administered for a long time, has a good blood drug concentration, and has a higher bioavailability than oral tablets. However, the oral patches prepared in Examples 6-9 cannot achieve the purpose of long-term administration.

[0086] In summary, when the combination of hydroxypropyl cellulose, hydroxyethyl cellulose and carboxymethyl cellulose is used in the present invention, the oral patch has good mechanical properties and demoulding properties, can be administered in the oral cavity for a long time, and more surprisingly, can significantly improve the mouthfeel of the oral patch. In addition, the oral patch of the present invention has a high drug loading rate and no drug precipitation.

[0088] Preparation Example 1:

[0089] (1) Add 1.3 g of a film-forming agent (composed of: 0.25 g of hydroxypropyl cellulose SL, 0.05 g of hydroxyethyl cellulose 250LR, and 1 g of carboxymethyl cellulose 7LPEP) to 38 g of an aqueous solution, stir, and continue to add 0.25 g of a plasticizer propylene glycol to obtain a polymer material mixed solution;

[0090] (2) adding 0.5 g of absorption enhancer SNAC and 0.6 g of semaglutide to the polymer material mixture and stirring to obtain a drug solution;

[0091] (3) The drug solution was evenly coated on the release film material using a coating machine, with a coating thickness of 0.8 mm. The backing material was a PET film, and the film was dried at 65° C. and demolded to obtain an oral patch.

[0092] Preparation Example 2:

[0093] (1) adding 1.3 g of a film-forming agent (composed of: 0.25 g of hydroxypropyl cellulose L, 0.05 g of hydroxyethyl cellulose 250LR, and 1 g of carboxymethyl cellulose 7LFPH) to 38 g of an aqueous solution, stirring, and continuously adding 0.25 g of a plasticizer propylene glycol to obtain a polymer material mixed solution;

[0094] (2) adding 0.5 g of absorption enhancer SNAC and 0.6 g of semaglutide to the polymer material mixture and stirring to obtain a drug solution;

[0095] (3) The drug solution was evenly coated on the release film material using a coating machine, with a coating thickness of 0.8 mm. The backing material was a PET film, and the film was dried at 65° C. and demolded to obtain an oral patch.

[0096] Preparation Example 3:

[0097] (1) Add 1.3 g of a film-forming agent (composed of: 0.25 g of hydroxypropyl cellulose M, 0.05 g of hydroxyethyl cellulose 250LR, and 1 g of carboxymethyl cellulose 7LPEP) to 38 g of an aqueous solution, stir, and continue to add 0.25 g of a plasticizer propylene glycol to obtain a polymer material mixed solution;

[0098] (2) adding 0.5 g of absorption enhancer SNAC and 0.6 g of semaglutide to the polymer material mixture and stirring to obtain a drug solution;

[0099] (3) The drug solution was evenly coated on the release film material using a coating machine, with a coating thickness of 0.8 mm. The backing material was a PET film, and the film was dried at 65° C. and demolded to obtain an oral patch.

[0100] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A semaglutide oral patch, comprising the following components by weight: 0.3-0.8 parts of semaglutide, 0.3-0.8 parts of absorption enhancer, 1-2 parts of film former and 0.2-0.5 parts of plasticizer; wherein: The film-forming agent consists of hydroxypropyl cellulose, hydroxyethyl cellulose and carboxymethyl cellulose.

2. The oral patch according to claim 1, characterized in that The composition comprises the following components in parts by weight: 0.4-0.7 parts of semaglutide, 0.3-0.6 parts of absorption enhancer, 1-1.5 parts of film former and 0.2-0.3 parts of plasticizer.

3. The oral patch according to claim 1, characterized in that The weight ratio of the hydroxypropyl cellulose, hydroxyethyl cellulose and carboxymethyl cellulose is 0.2-0.3:0.02-0.08:

1.

4. The oral patch according to claim 1, characterized in that The viscosity of the hydroxypropyl cellulose is 3-500 mPa.s; the viscosity of the hydroxyethyl cellulose is 100-200 mPa.s; and the viscosity of the carboxymethyl cellulose is 20-70 mPa.s.

5. The oral patch according to claim 1, characterized in that The mass content of semaglutide in the oral patch is 15%-30%.

6. The oral patch according to claim 1, characterized in that The total weight of the semaglutide, film-forming agent, absorption accelerator and plasticizer accounts for 90-100 wt % of the total weight of the oral patch.

7. The oral patch according to claim 1, characterized in that The plasticizer is selected from one or more of triethyl citrate, propylene glycol and glycerol.

8. A method for preparing the oral patch according to any one of claims 1 to 7, characterized in that: The following steps are involved: (1) adding a film-forming agent and a plasticizer to water to obtain a solution 1; (2) adding an absorption enhancer and semaglutide to solution 1 to obtain solution 2; (3) coating solution 2 on a release film material, drying, demoulding, and cutting to obtain the product.

9. The preparation method according to claim 8, characterized in that: The coating thickness in step (3) is 0.6-1.2 mm, and the drying temperature is 50-70°C.

10. Use of the oral patch according to any one of claims 1 to 7 or the oral patch prepared by the preparation method according to any one of claims 8 to 9 in preparing a drug for treating type II diabetes.

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