Smeglutide oral solid pharmaceutical composition and application thereof

Abstract

The invention provides a semeglutide oral solid pharmaceutical composition and application thereof. The composition comprises semeglutide, an absorption enhancer and other excipients. According to the absorption enhancer provided by the invention, the dissolution speed of the semeglutide in a preparation can be effectively controlled by adjusting the particle size distribution, and the bioavailability in vivo is further improved.

Description

Technical Field

[0001] The present disclosure relates to the field of pharmaceutical preparations, and in particular to a novel oral solid pharmaceutical composition of semaglutide and applications thereof. Background Art

[0002] GLP-1 receptor agonists are a class of hypoglycemic drugs that act on the GLP-1 receptors on pancreatic β cells. They have the effects of increasing insulin secretion, reducing glucagon secretion and reducing weight. They have become one of the effective methods for treating type 2 diabetes. Semaglutide belongs to the class of GLP-1 agonists and is mainly used clinically for patients with type 2 diabetes and cardiovascular disease, as well as type 2 diabetes patients whose blood sugar is still poorly controlled after receiving metformin and / or sulfonylurea drugs on the basis of diet control and exercise.

[0003] GLP-1 receptor agonists are mostly complex polypeptide macromolecular structures. Since polypeptides and proteins are easily inactivated by digestive enzymes and gastric acid, it is difficult for macromolecules to penetrate the gastrointestinal mucosa and their bioavailability is very low. Therefore, the main dosage form on the market is injection. However, injection therapy is an invasive and painful method of administration, which leads to low patient compliance. In September 2019, semaglutide tablets (trade name RYBELSUS) developed by Novo Nordisk were approved for marketing in the United States. This is the first oral preparation of GLP-1 receptor agonists on the market, which greatly increases patient compliance and is a leap in the history of GLP-1 receptor agonist treatment.

[0004] Chinese patent CN104203266B discloses a pharmaceutical composition comprising a first type of particles and a second type of particles and a method for preparing the composition. Chinese patent CN105963685B discloses a solid composition comprising a GLP-1 agonist and sodium N-(8-(2-hydroxybenzoyl)amino)caprylate (SNAC). Although there have been many reports on improvements to semaglutide tablets, its oral bioavailability is very low, only 0.4%-1.0%, which will inevitably lead to an increase in the number of medications used by patients, and correspondingly bring greater economic pressure. Therefore, it is urgent to find a solution to improve oral bioavailability. Summary of the invention

[0005] The present disclosure study found that the particle size range of the absorption enhancer N-(8-(2-hydroxybenzoyl)amino) sodium caprylate (SNAC) has a significant effect on the in vitro dissolution of orally administered peptides (especially GLP-1 peptides). Too large a particle size will lead to a decrease in the dissolution of orally administered peptides (especially GLP-1 peptides). Only by controlling the SNAC particle size within a certain range can the dissolution of orally administered peptides (especially GLP-1 peptides) meet the requirements. Therefore, in order to increase the dissolution rate of orally administered peptides (especially GLP-1 peptides), the SNAC particle size range should be appropriately controlled, thereby effectively controlling the dissolution rate of orally administered peptides (especially GLP-1 peptides) in the preparation, and further improving the bioavailability of orally administered peptides (especially GLP-1 peptides) in vivo.

[0006] The technical problem to be solved by the present disclosure is how to effectively improve the oral bioavailability of semaglutide. The present disclosure has found that the particle size range of the absorption enhancer N-(8-(2-hydroxybenzoyl)amino) sodium caprylate (SNAC) has a significant effect on the in vitro dissolution of orally administered peptides (especially GLP-1 peptides). The particle size in this specific range can increase the dissolution rate of the drug composition and improve the bioavailability.

[0007] In order to achieve the purpose of this disclosure, this disclosure adopts the following technical solutions:

[0008] A solid pharmaceutical composition for oral administration of semaglutide, the pharmaceutical composition comprising semaglutide, an absorption enhancer and an excipient, wherein the absorption enhancer is sodium N-(8-(2-hydroxybenzoyl)amino)caprylate (SNAC), and the particle size D90 of the absorption enhancer is in the range of about 10 μm to 100 μm. In some embodiments, the particle size D90 of the absorption enhancer is selected from about 10 μm, 15 μm, 20 μm, 25 μm, 30 μm, 35 μm, 40 μm, 45 μm, 50 μm, 55 μm, 60 μm, 65 μm, 70 μm, 75 μm, 80 μm, 85 μm, 90 μm, 95 μm, 100 μm or any value between any two numbers, preferably about 10 μm-60 μm, more preferably about 10 μm-30 μm, and most preferably about 10 μm-20 μm.

[0009] Further, in some embodiments, the particle size D50 of the absorption enhancer is in the range of about 5 μm to 50 μm, selected from about 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, 10 μm, 15 μm, 20 μm, 25 μm, 30 μm, 35 μm, 40 μm, 45 μm, 50 μm or any value between any two numbers, preferably about 5-30 μm, more preferably about 5-10 μm.

[0010] Further, in some embodiments, the particle size D10 of the absorption enhancer is in the range of about 2 μm to 20 μm, selected from about 2 μm, 2.5 μm, 3 μm, 3.5 μm, 4 μm, 4.5 μm, 5 μm, 5.5 μm, 6 μm, 6.5 μm, 7 μm, 7.5 μm, 8 μm, 8.5 μm, 9 μm, 9.5 μm, 10 μm, 15 μm, 20 μm or any value between any two numbers, preferably about 2-10 μm, more preferably about 2-5 μm.

[0011] Further, in some embodiments, the D90 of the absorption enhancer is in the range of about 10 μm-60 μm, the D50 of the absorption enhancer is in the range of about 5 μm-30 μm, and the D10 of the absorption enhancer is in the range of about 2 μm-10 μm.

[0012] Further, in some embodiments, the D90 of the absorption enhancer is in the range of about 10 μm-30 μm, the D50 of the absorption enhancer is in the range of about 5 μm-10 μm, and the D10 of the absorption enhancer is in the range of about 2 μm-5 μm.

[0013] The excipients include fillers, binders and lubricants, and the pharmaceutical composition is preferably a tablet.

[0014] Furthermore, the present disclosure also provides use of the above-mentioned pharmaceutical composition in preparing a drug for treating type 2 diabetes or obesity.

[0015] And, a treatment method, wherein an effective amount of the pharmaceutical composition is administered to a subject for treating type 2 diabetes or obesity.

[0016] The present invention discloses an oral solid pharmaceutical composition product of semaglutide prepared by using absorption enhancers SNAC with different particle sizes, and the in vitro accelerated stability test proves that the product quality is stable and controllable; the in vitro dissolution test proves that the product dissolution in vitro release rate of the absorption enhancer SNAC in a specific particle size range meets the requirements; the in vivo animal test proves that the absorption enhancer SNAC in a specific particle size range can effectively increase the exposure of semaglutide in vivo, has a higher in vivo bioavailability, and thus improves the compliance of medication. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 In vitro release profiles of semaglutide tablets formulated with absorption enhancer SNAC with different particle sizes DETAILED DESCRIPTION

[0018] the term

[0019] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0020] Before describing the present disclosure in detail below, it should be understood that the present disclosure is not limited to the specific methodology, scheme and reagent described herein, because these can change. It should also be understood that the terms used in this article are only for describing specific embodiments, and are not intended to limit the scope of the present disclosure. Unless otherwise defined, all technical and scientific terms used in this article have the same meaning as those of ordinary skill in the art to which the present disclosure belongs.

[0021] Certain embodiments disclosed herein include numerical ranges, and certain aspects of the present disclosure may be described in a range manner. Unless otherwise stated, it should be understood that numerical ranges or the manner of range description are only for the purpose of brevity and convenience, and should not be considered as a strict limitation of the scope of the present disclosure. Therefore, the description using the range manner should be considered to specifically disclose all possible sub-ranges and all possible specific numerical points within the range, as these sub-ranges and numerical points have been clearly written in this article. For example, the description from 1 to 6 should be considered to specifically disclose sub-ranges from 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., and specific numerical points within these ranges, such as 1, 2, 3, 4, 5, 6. Regardless of the width of the numerical value, the above principles are equally applicable. When using range description, the scope includes the endpoints of the scope.

[0022] When referring to measurable values ​​such as various quantities, temporal durations, and the like, the term "about" is meant to include variations of ±20%, or in some cases ±10%, or in some cases ±5%, or in some cases ±1%, or in some cases ±0.1% of the specified value.

[0023] The term "semaglutide" used herein, also known as N-ε26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butanoylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37), can be prepared by the method described in Example 4 of WO2006 / 097537.

[0024] The term "D10" used in this disclosure refers to the particle size corresponding to when the cumulative particle size distribution percentage of a sample reaches 10%. "D50" refers to the particle size corresponding to when the cumulative particle size distribution percentage of a sample reaches 50%. "D90" refers to the particle size corresponding to when the cumulative particle size distribution percentage of a sample reaches 90%. For those skilled in the art, there is a certain degree of error in particle size measurement. Generally speaking, plus or minus 10% is within a reasonable error range.

[0025] The term "bioavailability" as used herein refers to the fraction of an administered dose of an active pharmaceutical ingredient (API), such as semaglutide herein, that reaches the systemic circulation unchanged. By definition, when an API is administered intravenously, its bioavailability is 100%. However, when it is administered by other routes (e.g., orally), its bioavailability is reduced (due to incomplete absorption and first-pass metabolism).

[0026] The term "relative bioavailability" as used herein refers to the relative amount of active pharmaceutical ingredients absorbed into the systemic circulation obtained by a preparation administered by other extravascular routes (e.g., oral) as a reference preparation. According to the definition, when the reference preparation administers the API, its bioavailability is 100%. Relative bioavailability mainly reflects the effects of the dosage form, prescription, and preparation process of the test preparation on in vivo absorption compared with the reference preparation under a certain fixed route of administration (e.g., oral), and concentrates on the in vivo quality of the test preparation. The term "pharmaceutical composition" refers to a preparation or a combination of preparations containing one, two or more active ingredients, which allows the active ingredients contained therein to exist in a biologically effective form and does not contain additional ingredients that are unacceptably toxic to the subject to whom the preparation is administered. When a "pharmaceutical composition" exists in the form of a combination of separate preparations containing different, more than two active ingredients, it can be administered simultaneously, sequentially, separately, or at intervals, with the purpose of exerting the biological activity of multiple active ingredients and being used together to treat diseases.

[0027] Generally, the term "excipient" refers to any component other than the active therapeutic ingredient in a pharmaceutical composition, which may also be referred to as a "pharmaceutically acceptable carrier or excipient". An excipient may be an inert substance, an inactive substance and / or a substance without medical activity. Excipients may be used for various purposes, for example, as carriers, vehicles, fillers, adhesives, diluents, lubricants, glidants, disintegrants, antiadherents, flow control agents, crystallization retarders, solubilizers, stabilizers, colorants, flavor enhancers, surfactants, emulsifiers, and / or for improving the administration and / or absorption of active substances. In this article, "excipient" specifically refers to any other ingredient in an oral solid pharmaceutical composition except semaglutide and an absorption enhancer. Those skilled in the art can select one or more of the above excipients according to the specific desired properties of the solid oral dosage form, through routine tests and without any excessive burden. The amount of each excipient used may vary within the conventional range in the art.

[0028] The term "absorption enhancer" as used herein refers to a special excipient that can improve the absorption of a drug through the gastrointestinal mucosa. Other excipients of the pharmaceutical composition disclosed herein also include one or more of a filler, a binder, and a lubricant. Among them, the filler is preferably microcrystalline cellulose; the binder is preferably povidone; and the lubricant is preferably magnesium stearate.

[0029] The composition can be administered in several dosage forms, for example as a tablet, a coated tablet, a chewing gum, a capsule such as a hard or soft gelatin capsule, or a powder. The composition can be further compounded in a pharmaceutical carrier or a drug delivery system, for example to improve stability and / or solubility, or to further improve bioavailability. The composition can be a freeze-dried or spray-dried composition. The composition is preferably in the form of a tablet.

[0030] The term "effective amount" refers to the dosage of the solid pharmaceutical composition of the present disclosure, which produces the desired effect in the treated patient after being administered to the patient in a single or multiple doses. The effective amount can be easily determined by the attending physician who is a person skilled in the art by considering factors such as: racial differences; weight, age and health status; the specific disease involved; the severity of the disease; the response of the individual patient; the specific antibody administered; the mode of administration; the bioavailability characteristics of the administered formulation; the selected dosing regimen; and the use of any concomitant therapy.

[0031] The term "subject" as used herein refers to any animal, such as a mammal or marsupial. Individuals of the present disclosure include, but are not limited to, humans, non-human primates (e.g., cynomolgus monkeys or rhesus monkeys or other types of macaques), mice, pigs, horses, donkeys, cattle, sheep, rats, and poultry of any kind.

[0032] The term "treatment" as used herein refers to clinical intervention in an attempt to change the disease process caused by an individual or a cell, which can be either preventive or intervention in the clinical pathological process. The therapeutic effect includes, but is not limited to, preventing the occurrence or recurrence of the disease, alleviating symptoms, reducing any direct or indirect pathological consequences of the disease, preventing metastasis, slowing the progression of the disease, improving or alleviating the condition, alleviating or improving the prognosis, etc.

[0033] Example

[0034] The present disclosure is described in detail below by way of examples. It is necessary to point out that the following examples are only used to further illustrate the present disclosure and cannot be construed as limiting the scope of protection of the present disclosure. Some non-essential improvements and adjustments made by skilled personnel in the field according to the above-mentioned invention content still belong to the scope of protection of the present disclosure. If the specific conditions are not indicated in the examples, they are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not indicated, they are all conventional products that can be obtained through commercial purchase.

[0035] In order to further understand the present disclosure, a semaglutide oral solid pharmaceutical composition provided by the present disclosure is described in detail below in conjunction with preparation examples.

[0036] Preparation Example Preparation and Process of Pharmaceutical Compositions Containing SNAC with Different Particle Sizes

[0037] In this preparation example, semaglutide and SNAC and other pharmaceutical excipients are made into granules by a dry granulator, and then mixed with additional excipients and pressed into tablets.

[0038] Table 1 SNAC prescription composition information with different particle sizes

[0039]

[0040] Table 2 Preparation samples of SNAC with different particle sizes

[0041] SNAC particle size Sample A Sample B D90(μm) 13.572 52.534 D50(μm) 5.662 21.741 D10(μm) 2.343 8.604

[0042] Example 1 Dissolution Test

[0043] The in vitro release assay was performed as follows:

[0044] Refer to the dissolution and release determination method (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0931 Second Method). Dissolution conditions: Use 500 ml of phosphate buffer (pH 6.8) containing 0.05% brij35 (a surfactant) as the dissolution medium, the rotation speed is 70 revolutions per minute, operate according to the law, and take samples at 5, 10, 15, 30, 45 and 60 minutes respectively. Test solution: Take an appropriate amount of dissolution solution, filter, and take the filtrate. Determine according to high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0512). Chromatographic conditions: octadecylsilane bonded silica gel as filler (Sunfire C18, 4.6mm×150mm, 3.5μm or equivalent performance chromatographic column); 50mmol / L potassium dihydrogen phosphate solution (pH adjusted to 2.5 with phosphoric acid)-acetonitrile (55:45) as mobile phase; detection wavelength of 210nm; flow rate of 1.0ml per minute; column temperature of 40℃; injection volume of 20μl. Inject into liquid chromatograph respectively and record chromatogram. Calculate the dissolution amount of each tablet by peak area according to external standard method.

[0045] The results of in vitro release dissolution curve test are as follows:

[0046] Table 3 In vitro release dissolution curve results

[0047] Sample name 5min 10min 15min 30min 45min 60min Sample A 29 52 70 97 100 101 Sample B 30 53 70 95 95 96

[0048] From Table 3 and Figure 1 From the in vitro dissolution curve results shown, it can be seen that in the dissolution medium of pH 6.8, the dissolution results of sample A and sample B are basically the same, with no significant difference, and both meet the requirements.

[0049] Example 2 Animal Test

[0050] The animal experiment protocol is as follows:

[0051] Sixteen male and 16 female beagles were used in the study, weighing 6-11 kg during the study. A single dose was used and the administration was parallel. Fasting was performed for at least 12 hours before each administration, and about 15 ml of water was given immediately after each tablet administration, and fasting and water were withheld within 4 hours after administration. The composition was administered to each group of dogs by a single oral administration, each group including 2 male and 2 female dogs. Blood samples were collected at the following time points for the oral administration group: before administration and 0.25h, 0.5h, 1h, 1.5h, 2h, 4h, 8h, 24h, 48h, 72h, 120h, 168h and 216h after administration. The test sample information and results are as follows:

[0052] Table 4 Animal test sample information

[0053]

[0054] Table 5 Animal PK test data

[0055] Sample name Sample A Sample B SNAC particle size D90 (μm) 13.572 52.534 <![CDATA[C max (nM)]]> 324 187 <![CDATA[AUC last (nM.hr)]]> 15900 8190

[0056] Combined with the in vivo PK data of different samples in dogs shown in Table 5, when the SNAC particle size D90 increased from 13.572 μm to 52.534 μm, the bioavailability of sample A was nearly twice that of sample B, indicating that the particle size of the absorption enhancer SNAC has a significant effect on the in vivo absorption of semaglutide. A specific SNAC particle size range can improve the in vivo bioavailability of semaglutide.

[0057] Conclusion: The absorption enhancer SNAC in a specific particle size range disclosed in the present disclosure can effectively improve the bioavailability of the product in vivo, present an excellent delivery capability, and improve the compliance of medication. The in vitro dissolution test proves that the in vitro release rate of the product dissolution meets the requirements; at the same time, the preparation method disclosed in the present disclosure is simple, low-cost, and suitable for industrial promotion and application.

[0058] The embodiments of the present disclosure described above are exemplary only, and any person skilled in the art can recognize or determine the equivalents of numerous specific compounds, materials and operations without the need to carry out beyond routine experiments. All these equivalents are within the scope of the present disclosure and are included by the claims.

Claims

1. A solid pharmaceutical composition for oral administration of semaglutide, the pharmaceutical composition comprising semaglutide, an absorption enhancer and an excipient, the absorption enhancer being sodium N-(8-(2-hydroxybenzoyl)amino)caprylate (SNAC), and the particle size D90 of the absorption enhancer is in the range of about 10 μm to 60 μm.

2. The pharmaceutical composition according to claim 1, wherein the particle size D90 of the absorption enhancer is in the range of about 10 μm to 30 μm.

3. The pharmaceutical composition according to claim 1, wherein the particle size D50 of the absorption enhancer is in the range of about 5 μm to 30 μm. 4 . The pharmaceutical composition according to claim 1 , wherein the particle size D10 of the absorption enhancer is in the range of about 2 μm to 10 μm.

5. The pharmaceutical composition according to claim 1, wherein the particle size D90 of the absorption enhancer is in the range of about 10 μm to 30 μm, the particle size D50 of the absorption enhancer is in the range of about 5 μm to 10 μm, and the particle size D10 of the absorption enhancer is in the range of about 2 μm to 5 μm.

6. A pharmaceutical composition according to any preceding claim, wherein The pharmaceutical composition is in the form of a tablet.

7. A pharmaceutical composition according to any preceding claim, wherein The excipients include fillers, binders and lubricants.

8. Use of the pharmaceutical composition according to any one of the preceding claims in the preparation of a medicament for treating type 2 diabetes or obesity.

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