A pharmaceutical composition containing semaglutide and a preparation method thereof

Abstract

The application discloses a pharmaceutical composition containing semaglutide and a preparation method thereof. The pharmaceutical composition selects N-(5-chlorosalicyloyl)-8-aminooctanoate as an absorption promoter, has a simple prescription composition, improves the in-vivo bioavailability by improving the disintegration and dissolution, and is stable and reliable in quality, and is safer and more effective in clinical medication. Meanwhile, the preparation method is convenient, efficient and economical, and is beneficial to industrialized scale production.

Description

Technical Field

[0001] This invention relates to a pharmaceutical composition containing smegglutinin and its preparation method, and more particularly to a reliable, safe and effective pharmaceutical composition containing smegglutinin and its preparation method. Background Technology

[0002] GLP-1 (glucagon-like peptide-1) is a hormone secreted by the intestines after meals. Its main function is to promote insulin secretion, thereby lowering blood sugar levels. In addition, GLP-1 also inhibits gastric emptying and glucagon secretion, further reducing postprandial blood glucose spikes; suppresses the appetite center in the central nervous system, reducing food intake and weight; enhances the survival and function of cardiomyocytes, protecting the heart from ischemic damage; inhibits inflammatory responses and oxidative stress, improving endothelial function and arteriosclerosis; and stimulates the proliferation and differentiation of pancreatic islet cells, delaying the decline of pancreatic function.

[0003] Glucagon receptor agonists (GLP-1RAs) exert their hypoglycemic effect by activating GLP-1 receptors, stimulating insulin secretion and inhibiting glucagon secretion in a glucose concentration-dependent manner. They also increase glucose uptake in muscle and adipose tissue, inhibit hepatic glucose production, and thus suppress gastric emptying and appetite, thereby aiding in weight control. GLP-1 receptors are widely distributed in pancreatic islet cells, the gastrointestinal tract, lungs, brain, kidneys, hypothalamus, cardiovascular system, liver, adipocytes, and skeletal muscle.

[0004] Smegglutide is a GLP-1 receptor agonist with 94% structural homology to GLP-1 in vivo. CN107812181 discloses a pharmaceutical composition of smegglutide comprising two types of particles. The first type of particles consists of sodium N-(8-(2-hydroxybenzoyl)amino)octanoate (SNAC), magnesium stearate, and microcrystalline cellulose. The second type of particles consists of GLP-1 peptide, microcrystalline cellulose, and povidone. The two types of particles are granulated separately, then mixed, and finally compressed into tablets. This formulation has a complex composition. Because it contains two types of particles, separate granulation is required, resulting in high manufacturing costs and low efficiency. The prepared formulation exhibits slow release in in vitro dissolution media, relatively low in vivo bioavailability, and poor stability during long-term storage. Summary of the Invention

[0005] (a) Purpose of the invention: The primary objective of this invention is to provide a pharmaceutical composition containing smegglutinin and a method for preparing the same, comprising smegglutinin and N-(5-chlorosalicyloyl)-8-aminooctanoic acid metal salt. The pharmaceutical composition provided by this invention improves bioavailability in vivo, exhibits stable and reliable quality, and is safer and more effective for clinical use.

[0006] (II) Technical Solution: The present invention provides a pharmaceutical composition containing smegglutinin, comprising smegglutinin, N-(5-chlorosalicyloyl)-8-aminooctanoic acid metal salt, and a stabilizer.

[0007] In one embodiment, the metal salt of N-(5-chlorosalicyloyl)-8-aminooctanoic acid includes disodium salt of N-(5-chlorosalicyloyl)-8-aminooctanoic acid, dipotassium salt of N-(5-chlorosalicyloyl)-8-aminooctanoic acid, or calcium salt of N-(5-chlorosalicyloyl)-8-aminooctanoic acid.

[0008] In one embodiment, the metal salt of N-(5-chlorosalicyloyl)-8-aminooctanoate is disodium salt of N-(5-chlorosalicyloyl)-8-aminooctanoate (5-CNAC).

[0009] In one embodiment, the pharmaceutical composition comprises smegglutinin and disodium N-(5-chlorosalicyloyl)-8-aminooctanoate.

[0010] In one embodiment, the amount of smegglutinin is 10 to 20 parts by weight.

[0011] In one embodiment, the amount of smegglutinin is 14 parts by weight.

[0012] In one embodiment, the disodium N-(5-chlorosalicyloyl)-8-aminooctanoate is 250-350 parts by weight.

[0013] In one embodiment, the disodium N-(5-chlorosalicyloyl)-8-aminooctanoate is 300 parts by weight.

[0014] In one embodiment, the pharmaceutical composition comprises, by weight, 10-20 parts of smegglutinin and 250-350 parts of disodium N-(5-chlorosalicyloyl)-8-aminooctanoate.

[0015] In one embodiment, the pharmaceutical composition comprises, by weight, 14 parts of smegglutinin and 300 parts of disodium N-(5-chlorosalicyloyl)-8-aminooctanoate.

[0016] In one embodiment, the stabilizer comprises sodium dihydrogen phosphate, sodium bicarbonate, and / or potassium bisulfate.

[0017] In one embodiment, the stabilizer is sodium dihydrogen phosphate.

[0018] In one embodiment, the sodium dihydrogen phosphate is 30 to 60 parts by weight.

[0019] In one embodiment, the sodium dihydrogen phosphate is 45 parts by weight.

[0020] In one embodiment, the pharmaceutical composition further includes a lubricant.

[0021] In one embodiment, the lubricant comprises magnesium stearate, sodium stearate fumarate, carnauba wax, and / or polyethylene glycol 6000.

[0022] In one embodiment, the lubricant is magnesium stearate.

[0023] In one embodiment, the magnesium stearate is 7 to 8 parts by weight.

[0024] In one embodiment, the magnesium stearate is 7.7 parts by weight.

[0025] In one embodiment, the pharmaceutical composition comprises, by weight, smegglutinin, disodium N-(5-chlorosalicyloyl)-8-aminooctanoate, sodium dihydrogen phosphate, and magnesium stearate.

[0026] In one embodiment, the pharmaceutical composition comprises, by weight, 10-20 parts of smegglutide, 250-350 parts of disodium N-(5-chlorosalicyloyl)-8-aminooctanoate, 30-60 parts of sodium dihydrogen phosphate, and 7-8 parts of magnesium stearate.

[0027] In one embodiment, the pharmaceutical composition comprises, by weight, 14 parts of smegglutide, 300 parts of disodium N-(5-chlorosalicyloyl)-8-aminooctanoate, 45 parts of sodium dihydrogen phosphate, and 7.7 parts of magnesium stearate.

[0028] In another aspect, the present invention provides a pharmaceutical preparation comprising the above-described pharmaceutical composition.

[0029] In one embodiment, the dosage form of the pharmaceutical preparation is granules, lotion, liniment, aerosol, spray, elixir, ointment, suspension, infusion, tablet, suppository, injection, capsule, cream, lozenge, tincture, and / or paste.

[0030] In one embodiment, the dosage form of the pharmaceutical preparation is a tablet.

[0031] Peptide drugs are highly unstable after entering the body, easily metabolized or degraded by various enzymes, and can hardly pass through biological membranes to enter the body, resulting in very low bioavailability. This invention designs an oral solid pharmaceutical composition for semaglutide, specifically comprising the active pharmaceutical ingredient, the absorption enhancer N-(5-chlorosalicyloyl)-8-aminooctanoic acid disodium salt, the stabilizer sodium dihydrogen phosphate, and the lubricant magnesium stearate, and is compressed into tablets using direct powder compression or dry granulation processes.

[0032] The formulation and preparation process are relatively simple, enabling large-scale industrial production with low costs and high efficiency. The formulation exhibits rapid disintegration and dissolution, improving bioavailability, and demonstrates greater quality stability during long-term storage, thus enhancing the efficacy and safety of clinical use.

[0033] In one embodiment, the disintegration time of the pharmaceutical preparation is no more than 8 minutes.

[0034] The method for determining the disintegration time is as follows: Medium: 900ml water, medium temperature 37℃±0.5℃. After the medium temperature in the disintegrator cup is reached, put the 6-tablet drug composition into the lifting basket and record the sample disintegration time.

[0035] In one embodiment, the pharmaceutical formulation is tested using the following dissolution assay method, wherein the smegglutinin and the absorption enhancer have a cumulative dissolution content of not less than 85% after 15 minutes: Method: Paddle method, rotation speed: 50 rpm, dissolution medium temperature: 37℃±0.5℃, dissolution medium: 0.05M phosphate buffer with pH 6.8 and 0.05% m / m lauryl alcohol polyoxyethylene ether, dissolution medium volume: 500ml, sampling time: 5, 10, 15, 20, 30, 45 and 60 minutes, with replenishment after each sampling.

[0036] In another aspect, the present invention provides a method for preparing the above-mentioned pharmaceutical preparation: Method 1: Direct Powder Compression (1) Pre-treat the smegglutinin, absorption promoter, stabilizer and lubricant by sieving; (2) According to the dosage of the formulation, mix the pretreated smegglutinin, absorption promoter and stabilizer in step (1) evenly to obtain the premixed material; (3) According to the formulation prescription, mix the lubricant pretreated in step (1) with the premixed material obtained in step (2) evenly to obtain the final mixture. (4) Press the final mixture obtained in step (3) into sheets.

[0037] Method 2: Dry Granulation (1) Pre-treat the smegglutinin, absorption promoter, stabilizer and lubricant by sieving; (2) According to the dosage of the formulation, mix the pretreated smegglutinin, absorption promoter and stabilizer in step (1) evenly, compress into granules to obtain premixed granules; (3) According to the dosage of the formulation, mix the lubricant pretreated in step (1) with the premixed particles obtained in step (2) evenly to obtain the final mixed particles; (4) Compress the final mixed particles obtained in step (3) into tablets.

[0038] In step (1), the pretreatment involves passing the material through a 60-mesh sieve, and in step (4), the tableting hardness is 10 ± 2 kg. The dry granulation parameters for step (2) of method two are as follows: Feeding speed: 100 rpm, pressure roller speed: 10 rpm, cylinder pressure: 0.7 MPa, primary pelletizing speed: 80 rpm, secondary pelletizing speed: 300 rpm.

[0039] In another aspect, the present invention also provides a pharmaceutical preparation obtained by the above-described preparation method.

[0040] In another aspect, the present invention also provides a product comprising the above-described pharmaceutical composition and / or pharmaceutical preparation.

[0041] In another aspect, the present invention also provides the use of the above-described pharmaceutical compositions, pharmaceutical formulations and / or products in the preparation of medicaments for the prevention and / or treatment of diabetes, obesity, Alzheimer's disease, NASH and / or cardiovascular diseases.

[0042] (III) Beneficial Effects: Compared with the prior art, the present invention has the following significant advantages: 1. The pharmaceutical composition designed in this invention has a simple formulation, improves bioavailability in vivo by enhancing disintegration and dissolution, and has stable and reliable quality, making it safer and more effective for clinical use. Furthermore, the preparation method is convenient, efficient, and economical, facilitating large-scale industrial production. Attached Figure Description

[0043] Figure 1 The dissolution profiles of the active pharmaceutical ingredient contained in the formulations prepared for the examples and comparative examples are shown in a medium at pH 6.8. Figure 2 The dissolution curves of the absorption enhancers contained in the formulations prepared for the examples and comparative examples are shown in a medium at pH 6.8. Detailed Implementation

[0044] Terms and Definitions As used in this article, “containing,” “having,” or “including” includes “containing,” “mainly composed of,” “substantially composed of,” and “composed of”; “mainly composed of,” “substantially composed of,” and “composed of” are subordinate concepts of “containing,” “having,” or “including.”

[0045] As used herein, the terms “glucagon-like peptide-1” and “GLP-1” (which may be used interchangeably herein) refer to a polypeptide (as defined herein) that is a naturally occurring GLP-1 or an analogue thereof (e.g., a synthetic analogue). The analogue may be any derivative of naturally occurring GLP-1, such as a homologue (as defined herein), a fragment (containing a fragment of a homologue), and substituted derivatives of natural GLP-1 or its homologues and / or fragments thereof (e.g., containing substituents for improving stability and / or half-life), and / or modified in any other way as described herein with respect to the polypeptide. Preferably, the analogue exhibits the biological activity of GLP-1.

[0046] As used herein, the terms "absorption enhancer" and "absorption booster" are used interchangeably and refer to compounds known to enhance the absorption of large molecular weight drugs (e.g., compounds with a molecular weight of at least 1 kDa) from the gastrointestinal tract into circulation after oral administration. Those skilled in the art will recognize many such absorption enhancers.

[0047] In some embodiments of any of the examples described herein, the absorption enhancer is a fatty acid, optionally having a terminal N-(2-hydroxybenzoyl)amino group (at the ω position, i.e., at the end away from the carboxylic acid group of the fatty acid), or a salt thereof (e.g., a monosodium or disodium salt). Alternatively, the fatty acid may optionally be an unsubstituted fatty acid (e.g., hexanoic acid, caprylic acid, capric acid, lauric acid, oleic acid, and / or stearic acid).

[0048] The length of the fatty acid (substituted or unsubstituted) is preferably 4 to 20 carbon atoms, optionally 4 to 16 carbon atoms, optionally 4 to 14 carbon atoms, optionally 4 to 12 carbon atoms, or optionally 4 to 10 carbon atoms (including any intermediate values ​​and subranges therebetween). In some embodiments of any of the examples described herein, the length of the fatty acid (substituted or unsubstituted) is 6 to 20 carbon atoms, optionally 6 to 18 carbon atoms, optionally 6 to 16 carbon atoms, optionally 6 to 14 carbon atoms, optionally 6 to 12 carbon atoms, optionally 6 to 10 carbon atoms, and optionally 8 to 10 carbon atoms (including any intermediate values ​​and subranges therebetween). The fatty acid moiety can be saturated (e.g., octanoic acid in 8-N-(2-hydroxybenzoyl)aminooctanoic acid and decanoic acid in 10-N-(2-hydroxybenzoyl)aminodecanoic acid) or unsaturated (i.e., containing at least one unsaturated carbon-carbon bond).

[0049] Examples of suitable fatty acids (e.g., those substituted with terminal N-(2-hydroxybenzoyl)amino groups) include, but are not limited to, butyric acid, caprylic acid, and decanoic acid.

[0050] N-(2-hydroxybenzoyl)amino groups may optionally be substituted or unsubstituted (e.g., on their aromatic ring). Suitable substituents include, for example, halogens (optionally chlorinated) and alkoxy groups (optionally methoxy). Examples of substituted N-(2-hydroxybenzoyl)amino groups include, but are not limited to, N-(5-chlorosalicylicyl)amino, N-(4-chloro-2-hydroxybenzoyl)amino, and N-(2-hydroxy-4-methoxybenzoyl)amino.

[0051] Examples of suitable absorption enhancers include, but are not limited to, NAC (8-N-(2-hydroxybenzoyl)aminooctanoic acid) and NAD (10-N-(2-hydroxybenzoyl)aminodecanoic acid) and their salts (e.g., monosodium and disodium salts); and their derivatives (e.g., derivatives substituted with chlorine and / or methoxy groups), such as 5-CNAC (8-N-(5-chlorosalicyloyl)aminooctanoic acid) and 4-MOAC (8-N-(2-hydroxy-4-methoxybenzoyl)aminohexanoic acid) and their salts (e.g., monosodium and disodium salts). 4-CNAB (4-N-(2-hydroxy-4-chlorobenzoyl)aminobutyric acid) and its salts (e.g., monosodium and disodium salts) are additional examples of suitable absorption enhancers.

[0052] Each composition and unit dosage form described herein may optionally consist substantially of the functional ingredients as described above (e.g., therapeutic agents, absorption enhancers, and polymers containing basic groups according to any embodiment described in any relevant section of this document), or alternatively, the composition may further comprise a suitable pharmaceutically acceptable carrier and / or excipient.

[0053] As used herein, the term "pharmaceuticalally acceptable" refers to a substance that is suitable for use in humans and / or animals without excessive adverse effects (such as toxicity, irritation, and allergic reactions), i.e., a reasonable benefit / risk ratio.

[0054] As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to a carrier used for the administration of therapeutic agents, encompassing a variety of excipients and diluents. This term refers to pharmaceutical carriers that are not essential active ingredients themselves and do not cause excessive toxicity upon administration. Suitable carriers are well known to those skilled in the art, and a thorough discussion of pharmaceutically acceptable excipients can be found in Remington's Pharmaceutical Sciences (Mack Pub. Co., NJ 1991).

[0055] Pharmaceutically acceptable carriers in a composition include any and all solvents, dispersion media, preservatives, antioxidants, coatings, isotonic and absorption-delaying agents, surfactants, fillers, disintegrants, binders, diluents, lubricants, flow aids, pH adjusters, buffers, enhancers, wetting agents, solubilizers, surfactants, antioxidants, etc., compatible with drug administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The composition may contain other active compounds that provide complementary, additional, or enhanced therapeutic functions. Solid carriers or excipients, such as lactose, starch, or talc, or liquid carriers, such as water, fatty oils, or liquid paraffin, are possible. Other examples of carriers include culture media, such as DMEM or RPMI; and cryogenic storage media containing components that scavenge free radicals, provide pH buffering, osmotic / osmotic support, energy substrates, and ion concentrations to balance intracellular states at low temperatures; and mixtures of organic solvents with water.

[0056] The active substance in the product disclosed in this invention accounts for 0.001-99.9 wt% of the total weight of the composition. The balance consists of pharmaceutically acceptable carriers and other additives.

[0057] The dosage forms of the pharmaceutical compositions disclosed in this invention can be granules, lotions, liniments, aerosols, sprays, elixirs, ointments, suspensions, infusions, tablets, suppositories, injections, capsules, creams, lozenges, tinctures, and / or pastes.

[0058] The pharmaceutical compositions of the present invention can be administered using any known method. One of a variety of methods known to those skilled in the art can be used to administer the substance, compound, or agent to a subject using the terms "give" or "apply".

[0059] As used herein, the term “therapeutic effective dose” refers to a dose sufficient to treat a disease with a reasonable benefit / risk ratio suitable for medical treatment, and the effective dose level includes subject type and severity, age, sex, drug activity, drug sensitivity, time of administration, route of administration and excretion rate, duration of treatment, factors including concomitant drugs, and other factors known in the medical field.

[0060] As used herein, the term “treatment” for a symptom or patient refers to steps taken to achieve a beneficial or desired outcome, including clinical outcomes. Beneficial or desired clinical outcomes include, but are not limited to, eliminating, substantially inhibiting, slowing, or reversing the progression of a disease, symptom, or condition; substantially improving or alleviating the clinical or aesthetic symptoms of a symptom; substantially preventing the clinical or aesthetic symptoms of a disease, symptom, or condition; and avoiding harmful or unpleasant symptoms. Treatment also refers to achieving one or more of the following: (a) reducing the severity of the symptom; (b) limiting the development of characteristic symptoms of the symptom being treated; (c) limiting the exacerbation of characteristic symptoms of the symptom being treated; (d) limiting the recurrence of the symptom in patients who previously had the symptom; and / or (e) limiting the recurrence of symptoms in patients who previously did not have symptoms of the symptom.

[0061] The term "prevention" refers to reducing the likelihood of the onset (or recurrence) of a disease, disorder, condition, or associated symptoms.

[0062] In exemplary embodiments of the method disclosed herein, a dose of the drug, based on the subject's blood drug concentration, is subsequently administered to the subject during or after the initial time period. In an exemplary aspect, the dose subsequently administered after the initial time period is based on the subject's blood drug concentration measured or determined during the initial time period.

[0063] The blood concentration of a drug can be determined using any method known in the art. Suitable methods known in the art for determining the blood concentration of a drug include, for example, gas chromatography (GC), high-performance liquid chromatography (HPLC), high-performance liquid chromatography-mass spectrometry (HPLC-MS), liquid chromatography-mass spectrometry (LCMS), immunoassays (e.g., competitive immunoassays, immunoassays, fluorescence polarization immunoassays (FPIA), enzyme immunoassays (EMIT), and enzyme-linked immunosorbent assays (ELISA)) or combinations thereof. See, for example, Wang et al., Nan Fan Yi Ke Da Xue Xue Bao [Journal of Southern Medical University] 28(11): 1993-1995 (2008); Dasgupta and Datta, Handbook of Drug Monitoring Methods, Chapter 3: Analytical Techniques for Measuring Concentrations of Therapeutic Drugs in Biological Fluids, pp. 67-86 (2008); Kang and Lee, Korean J Intern Med [Korean Journal of Internal Medicine] 24(1): 1-10 (2009); Glazko, Antiepileptic Drugs, 3rd ed., New York: Raven Press, 1989, pp. 159-176; and Steijns et al., TherDrug Monit [Therapeutic Drug Monitoring] 24:432-435 (2002). In an exemplary aspect, the method includes determining blood drug concentrations by performing LC-MS / MS or quantitative microsphere assays. In an exemplary aspect, the method includes determining blood drug concentrations by a competitive immunoassay, wherein free drug in a plasma sample competes with drug molecules coated on uniform microparticles for antibody binding sites. In an exemplary aspect, blood drug concentrations are determined using a QMS™ Therapeutic Drug Monitoring (TDM) assay, a CEDIA™ Therapeutic Drug Monitoring (TDM) assay, or a DRIT™ TDM assay (Thermo Fisher Scientific, Waltham, MA).

[0064] As used herein, the term "disintegration" refers to the reduction of an object into components, fragments, or particles. Disintegration time can be measured in vitro or in vivo. Unless otherwise stated, in vitro measurements are performed in accordance with European Pharmacopeia 9.0, section 2.9.1, "Disintegration of tablets and capsules".

[0065] The pharmacokinetics of a drug can be described using in vitro dissolution-in vivo absorption correlation (IVIVC). For example, IVIVC is often defined by the U.S. Food and Drug Administration (FDA) as a predictive mathematical model describing the relationship between the in vitro properties of a dosage form and its in vivo response. Typically, in vitro properties can be the rate or extent of drug dissolution or release, while in vivo responses can be plasma drug concentrations or the amount of drug absorbed. The United States Pharmacopeia (USP) also defines IVIVC as the establishment of a relationship between a biological characteristic of a dosage form, or a parameter derived from a biological characteristic, and the physicochemical characteristics of the same dosage form. Typically, parameters derived from biological properties can be, for example, AUC or Cmax, while physicochemical properties can be in vitro dissolution characteristics.

[0066] As used herein, the terms "immediate release" or "conventional release" refer to the release of an active substance from a pharmaceutical composition that is not intentionally modified by a particular formulation design and / or method of manufacture. For oral dosage forms, this means that the dissolution profile of the active substance is substantially dependent on the inherent properties of the active substance. Generally, the terms "immediate release" or "conventional release" refer to a pharmaceutical composition that releases >75% (by weight) of the active pharmaceutical ingredient in vitro at 45 minutes.

[0067] As used herein, the terms "extended release" and "controlled release" refer to a pharmaceutical composition exhibiting a slower release of the active agent than a conventionally released pharmaceutical composition administered via the same route. Extended or controlled release is achieved through specific formulation design and / or manufacturing methods. Generally, the terms "extended release" and "controlled release" refer to a pharmaceutical composition that releases ≤75% (by weight) of the active agent in vitro at 45 minutes.

[0068] As used herein, the term “bioavailability” refers to the extent to which a drug or other substance reaches the target tissue after administration.

[0069] Generally, it is known that after oral administration, various factors can affect the absorption and bioavailability of therapeutically active substances. These factors include the presence of food in the gastrointestinal tract; generally, the residence time of a drug in the stomach is significantly longer in the presence of food than in a fasting state. If the bioavailability of a drug is affected beyond a certain point due to the presence of food in the gastrointestinal tract, then the drug is considered to exhibit a food effect. The food effect is important because of the risk associated with administering the drug to a patient who has just eaten. This risk stems from the possibility that the absorption of the drug into the bloodstream may be adversely affected, such that the patient may not achieve sufficient absorption to treat the condition for which the drug is intended. In the case of, for example, compositions, the situation is different because food increases its absorption. Therefore, not consuming food while using the drug can lead to insufficient absorption.

[0070] The composition exhibits suitable bioavailability of the active compound and / or reduces or eliminates the food effect.

[0071] As used herein, the term "suitable bioavailability" means that the administration of the compositions of the present invention will produce improved bioavailability compared to that obtained after administration of the active substance in a conventional tablet; or that the bioavailability is at least the same or improved compared to that obtained after administration of a commercially available product containing the same active substance in the same amount. A more complete absorption of the active substance is particularly desirable, thereby potentially reducing the dosage. Furthermore, pharmaceutical compositions and dosage forms containing semaglutide may reduce or eliminate the need for food intake with the dosage form, thus allowing patients greater freedom in the timing of medication. Similarly, improved or increased bioavailability leads to improved treatment, as the same therapeutic response and more stable plasma levels may be obtained with reduced doses and / or fewer administrations, and without food restrictions. Another way to achieve improvement in a disease (which requires, for example, a composition to treat) is by balancing the release of the composition into the gastrointestinal tract in such a way that an increased plasma concentration of the composition is obtained immediately after administration or an increased plasma concentration of the composition is obtained with a delay, i.e., by using a modified or delayed release composition containing one or more smegglutinins.

[0072] Unless otherwise specified, the experimental methods used in the following examples are conventional methods, and the reagents, methods and equipment used are conventional reagents, methods and equipment in this technical field.

[0073] The technical solution of the present invention will be further described below with reference to the embodiments.

[0074] Example 1: Blood drug concentrations in rats after administration of a mixture of different glucagon-like peptide-1 (GLP-1) analogs and 5-CNAC: 5-CNAC was mixed with exenatide, liraglutide and dulaglutide, respectively, and then administered to rats by gavage.

[0075] Animal administration: Six rats were randomly assigned to each group, half male and half female. The same amount of the drug composition was administered by gavage to each group.

[0076] Sample processing: Blood samples were collected at the following time points: 0 h before drug administration, and 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h, and 24 h after drug administration. Whole blood was collected into centrifuge tubes containing anticoagulant, stored on ice, and centrifuged at 2–8 °C, 4000 rpm for 10 min. Plasma was collected into separately labeled EP tubes and stored at -70 ± 10 °C.

[0077] Data analysis: The concentration of the active pharmaceutical ingredient in the biological samples was determined by LC-MS / MS, and the bioanalytical data were subjected to pharmacokinetic analysis. The results are shown in Table 1.

[0078] Table 1. Blood concentrations of GLP-1 analogues administered via gavage in rats. As shown in Table 1, 5-CNAC has a much lower effect on promoting the blood concentration of other GLP-1 analog peptides such as exenatide, liraglutide and dulaglutide in rats than smegglutide.

[0079] Example 2: Compatibility Study of Raw Materials and Auxiliary Materials Referring to the original formulation (Smegglutide tablets (Novo Nordisk), Novo Nordisk), the same type of excipients were selected. In accordance with the relevant methods of compatibility study in the "Basic Technical Guidelines for Research on Chemical Drug Preparations", and combined with the actual situation of the drug composition of this invention, the active pharmaceutical ingredient (Smegglutide) and excipients were mixed in a certain proportion and placed under high temperature (40℃, 60℃) and high humidity (92.5%RH, 25℃) conditions for 30 days. Samples were taken at 10 days and 30 days to investigate the changes in the properties of the active pharmaceutical ingredient and related substances. The results are shown in Figure 2 and Table 3.

[0080] Table 2 Results of the compatibility study of raw materials and auxiliary materials (properties) Table 3. Results of the compatibility study of raw materials and auxiliary materials (related substances) As shown in Tables 2 and 3, semaglutide, microcrystalline cellulose, and povidone exhibited a darkening of color and a significant increase in related substances under high-temperature conditions. Under high-humidity conditions, there was a noticeable increase in weight due to moisture absorption, leading to a tendency for related substances to rise. Compared to the original formulation, the pharmaceutical composition designed in this invention shows good compatibility between semaglutide and 5-CNAC, with less increase in related substances. Furthermore, the overall stability is further improved by adding the stabilizer sodium dihydrogen phosphate.

[0081] Example 3: Preparation of tablets using direct powder compression process: (1) Formulation (10,000 tablets): (2) Formulation process: Raw material pretreatment: Pass the active pharmaceutical ingredient (Smegglutide), 5-CNAC, sodium dihydrogen phosphate, and magnesium stearate through a 60-mesh sieve for later use.

[0082] Weighing: Weigh the prescribed amounts of the raw materials, 5-CNAC, sodium dihydrogen phosphate, and magnesium stearate for later use.

[0083] Premixing: Place the weighed raw materials, 5-CNAC, and sodium dihydrogen phosphate into a mixer and mix for 40 minutes to obtain mixture 1.

[0084] Total mixture: Add the prescribed amount of magnesium stearate to mixture 1 and mix for 20 minutes to obtain mixture 2.

[0085] Intermediate content determination: Take 2 samples of the mixture and determine the intermediate content.

[0086] Tableting: Place the mixture 2 into the tablet press hopper, calculate the tablet weight based on the intermediate content, and use a 7.5×13.5mm elliptical punch to compress the tablets. The tablet hardness is approximately 10kg.

[0087] Example 4: Preparation of tablets using a dry granulation process: (1) Formulation (10,000 tablets): (2) Formulation process: Raw material pretreatment: Pass the active pharmaceutical ingredient, 5-CNAC, sodium dihydrogen phosphate, and magnesium stearate through a 60-mesh sieve for later use.

[0088] Weighing: Weigh the prescribed amounts of the raw materials, 5-CNAC, sodium dihydrogen phosphate, and magnesium stearate for later use.

[0089] Premixing: Place the weighed raw materials, 5-CNAC, and sodium dihydrogen phosphate into a mixer and mix for 40 minutes to obtain mixture 1.

[0090] Dry pelleting: The mixture 1 is dry-granulated using a pellet mill. The dry pelleting parameters are: feeding speed 100 rpm, pressure roller speed 10 rpm, cylinder pressure 0.7 MPa, first-stage pelletizing speed 80 rpm, and second-stage pelletizing speed 300 rpm to obtain dry pellets.

[0091] Total mixture: Add the prescribed amount of magnesium stearate to the dry granules and mix for 20 minutes to obtain mixture 2.

[0092] Intermediate content determination: Take 2 samples of the mixture and determine the intermediate content.

[0093] Tableting: Place the mixture 2 into the tablet press hopper, calculate the tablet weight based on the intermediate content, and use a 7.5×13.5mm elliptical punch to compress the tablets. The tablet hardness is approximately 10kg.

[0094] Comparative Example 1 Original Reagent: Comparative Example 1 is the original formulation (Novo Nordisk), manufacturer: Novo Nordisk, batch number: NJG6599, specification: 14mg, the same below.

[0095] Comparative Example 2: SNAC replaces 5-CNAC: (1) Formulation (10,000 tablets): (2) Formulation process: Raw material pretreatment: Pass the active pharmaceutical ingredient, SNAC, sodium dihydrogen phosphate, and magnesium stearate through a 60-mesh sieve for later use.

[0096] Weighing: Weigh the prescribed amounts of the raw materials, SNAC, sodium dihydrogen phosphate, and magnesium stearate for later use.

[0097] Premixing: Place the weighed raw materials, SNAC, and sodium dihydrogen phosphate into a mixer and mix for 40 minutes to obtain mixture 1.

[0098] Dry pelleting: The mixture 1 is dry-granulated using a pellet mill. The dry pelleting parameters are: feeding speed 100 rpm, pressure roller speed 10 rpm, cylinder pressure 0.7 MPa, first-stage pelletizing speed 80 rpm, and second-stage pelletizing speed 300 rpm to obtain dry pellets.

[0099] Total mixture: Add the prescribed amount of magnesium stearate to the dry granules and mix for 20 minutes to obtain mixture 2.

[0100] Intermediate content determination: Take 2 samples of the mixture and determine the intermediate content.

[0101] Tableting: Place the mixture 2 into the tablet press hopper, calculate the tablet weight based on the intermediate content, and use a 7.5×13.5mm elliptical punch to compress the tablets. The tablet hardness is approximately 10kg.

[0102] Comparative Example 3: Stabilizer omitted. (1) Formulation prescription (10,000 tablets) (2) Formulation process Raw material pretreatment: Pass the active pharmaceutical ingredient, 5-CNAC, and magnesium stearate through a 60-mesh sieve for later use.

[0103] Weighing: Weigh the prescribed amounts of the raw materials, 5-CNAC, and magnesium stearate for later use.

[0104] Premixing: Place the weighed raw materials and 5-CNAC into a mixer and mix for 40 minutes to obtain mixture 1.

[0105] Dry pelleting: The mixture 1 is dry-granulated using a pellet mill. The dry pelleting parameters are: feeding speed 100 rpm, pressure roller speed 10 rpm, cylinder pressure 0.7 MPa, first-stage pelletizing speed 80 rpm, and second-stage pelletizing speed 300 rpm to obtain dry pellets.

[0106] Total mixture: Add the prescribed amount of magnesium stearate to the dry granules and mix for 20 minutes to obtain mixture 2.

[0107] Intermediate content determination: Take 2 samples of the mixture and determine the intermediate content.

[0108] Tableting: Place the mixture 2 into the tablet press hopper, calculate the tablet weight based on the intermediate content, and use a 7.5×13.5mm elliptical punch to compress the tablets. The tablet hardness is approximately 10kg.

[0109] Comparative Example 4: Sodium carbonate replaces sodium dihydrogen phosphate: (1) Formulation prescription (10,000 tablets) (2) Formulation process Raw material pretreatment: Pass the active pharmaceutical ingredient, 5-CNAC, povidone, sodium carbonate, and magnesium stearate through a 60-mesh sieve for later use.

[0110] Weighing: Weigh the prescribed amounts of the raw materials, 5-CNAC, povidone, sodium carbonate, and magnesium stearate for later use.

[0111] Premixing: Weigh the raw materials, 5-CNAC, povidone, and sodium carbonate and mix them in a mixer for 40 minutes to obtain mixture 1.

[0112] Total mixing: Add the prescribed amount of magnesium stearate to material 1 and mix for 20 minutes to obtain mixture material 2.

[0113] Intermediate content determination: Take 2 samples of the mixture and determine the intermediate content.

[0114] Tableting: Place the mixture 2 into the tablet press hopper, calculate the tablet weight based on the intermediate content, and use a 7.5×13.5mm elliptical punch to compress the tablets. The tablet hardness is approximately 10kg.

[0115] Comparative Example 5: Sodium bicarbonate replaces sodium dihydrogen phosphate: (1) Formulation prescription (10,000 tablets) (2) Formulation process Raw material pretreatment: Pass the active pharmaceutical ingredient, 5-CNAC, povidone, sodium bicarbonate, and magnesium stearate through a 60-mesh sieve for later use.

[0116] Weighing: Weigh the prescribed amounts of the raw materials, 5-CNAC, povidone, sodium bicarbonate, and magnesium stearate for later use.

[0117] Premixing: Place the weighed raw materials, 5-CNAC, povidone, and sodium bicarbonate into a mixer and mix for 40 minutes to obtain mixture 1.

[0118] Total mixing: Add the prescribed amount of magnesium stearate to material 1 and mix for 20 minutes to obtain mixture material 2.

[0119] Intermediate content determination: Take 2 samples of the mixture and determine the intermediate content.

[0120] Tableting: Place the mixture 2 into the tablet press hopper, calculate the tablet weight based on the intermediate content, and use a 7.5×13.5mm elliptical punch to compress the tablets. The tablet hardness is approximately 10kg.

[0121] Example 5: Evaluation of the disintegration time of the formulation: (1) Measurement method: The test was conducted according to the 2020 edition of the Chinese Pharmacopoeia, Part IV, 0921, Disintegration Time Test Method. A lift-type disintegration apparatus was used for testing. Six tablets were taken for each test, and 900 ml of water at 37°C was used as the medium. After the medium in the container reached the set temperature, the tablets were placed into the lift-type basket, and the disintegration time was recorded.

[0122] (2) Measurement results: Table 4 Comparison of Disintegration Time Limits As can be seen from Table 4, the formulations prepared in the examples have a faster disintegration rate, while the comparative formulations have a longer disintegration time.

[0123] Example 6: In vitro dissolution evaluation of the formulation: (1) Measurement method: According to the 2020 edition of the Chinese Pharmacopoeia, Part IV, 0931, and the "Technical Guidelines for Dissolution and Release Determination and Dissolution Testing of Common Oral Solid Dosage Forms," ​​a paddle method was used at a rotation speed of 50 rpm. 500 ml of 0.05 M phosphate buffer (pH 6.8) containing 0.05% lauryl alcohol polyoxyethylene ether (Brij35) was used at 37 ± 0.5 °C. Aliquots of the sample were collected at time points of 5, 10, 15, 20, 30, 45, and 60 min. The release of the active pharmaceutical ingredient (semaglutide), 5-CNAC, and SNAC in the dissolution medium was analyzed using HPLC.

[0124] (2) Measurement results: Table 5. Results of in vitro dissolution comparison From Table 5, Figure 1 and Figure 2 As can be seen, the cumulative dissolution of the active pharmaceutical ingredient and 5-CNAC in the formulation prepared in the example reached more than 85% at 15 min, indicating a relatively fast dissolution rate, and both were eventually completely dissolved; the comparative example showed slower dissolution and could not be completely dissolved under the test conditions.

[0125] Example 7: Evaluation of the in vivo bioavailability of the formulation Animal administration: Six beagle dogs were randomly assigned to each group, half male and half female. The same amount of the drug composition was administered by gavage to each group.

[0126] Sample processing: Blood samples were collected at the following time points: 0 h before drug administration, and 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h, and 24 h after drug administration. Whole blood was collected into centrifuge tubes containing anticoagulant, stored on ice, and centrifuged at 2–8 °C, 4000 rpm for 10 min. Plasma was collected into separately labeled EP tubes and stored at -70 ± 10 °C.

[0127] Data analysis: The concentration of the active pharmaceutical ingredient in the biological samples was determined by LC-MS / MS, and the bioanalytical data were subjected to pharmacokinetic analysis. The results are shown in Table 6.

[0128] Table 6 Comparison of in vivo pharmacokinetic parameters As can be seen from Table 6, Formulation C prepared in Example 3 max Formulation C was prepared in Example 4 at 241% of Comparative Example 2. max Compared to Comparative Example 2, which showed a 269% improvement, the pharmaceutical composition designed in this invention significantly increased the oral plasma concentration compared to the composition using SNAC. Meanwhile, formulations C prepared in Comparative Examples 4 and 5... maxComparative Example 3 demonstrates that sodium dihydrogen phosphate in the pharmaceutical composition designed in this invention significantly increases the oral blood drug concentration compared to the combination of sodium carbonate and sodium bicarbonate.

[0129] Example 8: Evaluation of the quality stability of the formulation: (1) Measurement method: According to the 2020 edition of the Chinese Pharmacopoeia, Volume IV, 0512, the contents of the active pharmaceutical ingredient smegglutinin, 5-CNAC in the examples, SNAC in the comparative examples, and related substances were determined using HPLC.

[0130] The prepared samples of Example 3, Example 4 and comparative examples were placed in a constant temperature and humidity chamber at 40±2℃ and 75%±5% for accelerated stability testing. Samples were taken at 0, 1, 2, 3 and 6 months to determine the content of active pharmaceutical ingredient and absorption enhancer in the examples and comparative examples, as well as the growth of related substances in the formulations.

[0131] (2) Measurement results: Table 7. Accelerated stability comparison results (content of active ingredient and absorption enhancer) Table 8. Comparison of Accelerated Stability (Content of Relevant Substances) As can be seen from Tables 7 and 8, compared with the original formulation, the drug composition designed in this invention has more stable content of active pharmaceutical ingredient and absorption enhancer in stability studies, and less growth of formulation-related substances, resulting in better overall stability and ensuring the effectiveness of clinical administration.

Claims

1. A pharmaceutical composition containing smegglutinin, characterized in that, It contains smegglutinin, N-(5-chlorosalicyloyl)-8-aminooctanoic acid metal salt and stabilizer.

2. The pharmaceutical composition according to claim 1, characterized in that, The metal salts of N-(5-chlorosalicyloyl)-8-aminooctanoate include disodium salt of N-(5-chlorosalicyloyl)-8-aminooctanoate, dipotassium salt of N-(5-chlorosalicyloyl)-8-aminooctanoate, and / or calcium salt of N-(5-chlorosalicyloyl)-8-aminooctanoate.

3. The pharmaceutical composition according to claim 2, characterized in that, The N-(5-chlorosalicyloyl)-8-aminooctanoic acid metal salt is the disodium salt of N-(5-chlorosalicyloyl)-8-aminooctanoic acid.

4. The pharmaceutical composition according to claim 1, characterized in that, The stabilizer includes sodium dihydrogen phosphate, sodium bicarbonate, and / or sodium carbonate.

5. The pharmaceutical composition according to claim 4, characterized in that, The stabilizer is sodium dihydrogen phosphate.

6. The pharmaceutical composition according to any one of claims 1-5, characterized in that, The pharmaceutical composition comprises, by weight, 10-20 parts of smegglutide, 250-350 parts of N-(5-chlorosalicyloyl)-8-aminooctanoic acid metal salt, and 30-60 parts of stabilizer.

7. The pharmaceutical composition according to claim 6, characterized in that, The pharmaceutical composition comprises, by weight, 14 parts of smegglutide, 300 parts of N-(5-chlorosalicyloyl)-8-aminooctanoic acid metal salt, and 45 parts of stabilizer.

8. The pharmaceutical composition according to any one of claims 1-5, characterized in that, The pharmaceutical composition also includes a lubricant.

9. The pharmaceutical composition according to claim 8, characterized in that, The lubricant includes magnesium stearate, sodium stearate fumarate, carnauba wax, and / or polyethylene glycol 6000.

10. The pharmaceutical composition according to claim 9, characterized in that, The lubricant is magnesium stearate.

11. The pharmaceutical composition according to claim 10, characterized in that, The pharmaceutical composition further includes, by weight, 7-8 parts of magnesium stearate.

12. The pharmaceutical composition according to claim 11, characterized in that, The pharmaceutical composition further includes, by weight, 7.7 parts magnesium stearate.

13. The pharmaceutical composition according to any one of claims 1-5, characterized in that, The pharmaceutical composition also includes a pharmaceutically or immunologically acceptable carrier or excipient.

14. A pharmaceutical preparation, characterized in that, The pharmaceutical composition comprises any one of claims 1-13.

15. The pharmaceutical preparation according to claim 14, characterized in that, The pharmaceutical preparation comprises the pharmaceutical composition according to any one of claims 8-12.

16. The pharmaceutical preparation according to claim 14 or 15, characterized in that, The dosage forms of the pharmaceutical preparations include granules, lotions, liniments, aerosols, sprays, elixirs, ointments, suspensions, infusions, tablets, suppositories, injections, capsules, creams, lozenges, tinctures, and / or pastes.

17. The pharmaceutical preparation according to claim 16, characterized in that, The dosage form of the pharmaceutical preparation is a tablet.

18. A method for preparing a pharmaceutical formulation as described in claim 15, characterized in that, include: (1) Smegglutinin, N-(5-chlorosalicyloyl)-8-aminooctanoic acid metal salt, stabilizer and lubricant were pretreated by sieving; (2) According to the dosage of the formulation, mix the pretreated smegglutinin, N-(5-chlorosalicyloyl)-8-aminooctanoic acid metal salt and stabilizer in step (1) evenly to obtain the premixed material; (3) According to the formulation prescription, mix the lubricant pretreated in step (1) with the premixed material obtained in step (2) evenly to obtain the final mixture. (4) Press the final mixture obtained in step (3) into sheets.

19. A method for preparing a pharmaceutical formulation as described in any one of claims 15, characterized in that, It includes: (1) Smegglutinin, N-(5-chlorosalicyloyl)-8-aminooctanoic acid metal salt, stabilizer and lubricant were pretreated by sieving; (2) According to the dosage of the formulation, mix the pretreated smegglutinin, N-(5-chlorosalicyloyl)-8-aminooctanoic acid metal salt and stabilizer in step (1) evenly, compress into granules, and obtain premixed granules; (3) According to the dosage of the formulation, mix the lubricant pretreated in step (1) with the premixed particles obtained in step (2) evenly to obtain the final mixed particles; (4) Compress the final mixed particles obtained in step (3) into tablets.

20. A pharmaceutical preparation, characterized in that, Obtained by the preparation method described in claim 18 or 19.

21. A product, characterized in that, Includes the pharmaceutical composition according to any one of claims 1-13, the pharmaceutical formulation according to any one of claims 14-17, or the pharmaceutical preparation according to claim 20.

22. Use of the pharmaceutical composition of any one of claims 1-13, the pharmaceutical preparation of any one of claims 14-17 or claim 20 and / or the product of claim 21 in the preparation of a medicament for the prevention and / or treatment of diabetes, obesity, Alzheimer's disease, NASH and / or cardiovascular disease.

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