WO2018121702A1 - Pharmaceutical composition of glp-1 analogue and preparation method therefor - Google Patents

Abstract

A pharmaceutical composition of a GLP-1 analogue and a preparation method therefor. Specifically, the present invention relates to a pharmaceutical composition containing a GLP-1 receptor agonist and a salt of N-(8-(2-hydroxyphenylmethyl)amino)octanoic acid (NAC), the pharmaceutical composition having a relatively short disintegration time and an excellent dissolution rate.

Description

Pharmaceutical composition of GLP-1 analogue and preparation method thereof Technical field

The present invention belongs to the field of pharmaceutical preparations, and in particular to a pharmaceutical composition comprising a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof.

Background technique

Type 2 diabetes has become a serious global health problem, with a rapid increase in prevalence and 80% of patients from low- and middle-income countries. According to the World Diabetes Federation (IDF), in 2013, China's diabetes patients reached 98.4 million, ranking first in the world. Among the patients in China, type II diabetes is the main cause, accounting for more than 90.0%, and most patients have poor control. Therefore, the treatment of diabetes still faces enormous challenges. Changes in the intestinal environment, especially the changes in intestinal hormone levels and effects in the pathogenesis of diabetes, are receiving increasing attention from experts. The change of incretin level and function during the onset of type II diabetes has become a hot topic in the current treatment of diabetes. Therefore, incretin-based treatment has become one of the hotspots in the field of diabetes research in recent years. It is different from the unique mechanism and benefits of traditional hypoglycemic drugs, opening up new ways for the treatment of diabetes.

Incretin is mainly composed of GLP-1 (insulinotropic peptide-1) and GIP (glucose-dependent insulinotropic polypeptide), and current incretin-based treatment is mainly divided into two major categories, DPP-4 inhibitors ( Such as sitagliptin) and GLP-1 receptor agonists (such as exenatide and liraglutide), while exenatide has more effective hypoglycemic effect than liraglutide and sitagliptin It is more obvious to improve the characteristics of β-cell function.

GLP-1 is a gut peptide hormone secreted mainly by the terminal ileum, colon and rectal mucosal L cells, which is also compatible with the existing site of absorption promotion technology.

The half-life of natural GLP-1 is very short, only 1 to 2 min. After release, it is rapidly decomposed by dipeptidyl peptidase-4 (DPP-4) and loses its insulin-promoting activity, which cannot reach the therapeutic concentration level of type 2 diabetes. In order to be suitable for clinical long-term application, plasma levels and potency can be increased in two ways: first, structural modification of GLP-1 makes it less susceptible to rapid degradation by DPP-4; second, inhibition of DPP-4 activity, thereby Delay the degradation of endogenous GLP-1. Currently, there are two types of drugs based on these two research and development strategies, one is DPP-4 inhibitor and the other is GLP-1 receptor agonist. Both types of drugs have been listed in China, and some clinical research has been carried out.

CN101987868B discloses a short-acting GLP-1 analogue which is a synthetic GLP-1 derivative containing a palmitic acid structure, the main peptide chain consisting of 40 amino acids. It has high development value, and has a structure of HOOC(CH2)14-CO-lipophilic substituent and the α-amino group or ε-amino group of the C-terminal Lys of the following amino acid sequence is linked by an amide bond.

His-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Glu-Glu-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp- Leu-Val-Arg-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys.

WO2003072195 discloses an oral formulation comprising a GLP-1 analogue and a specific delivery agent, wherein the delivery agent increases the dissolution and bioavailability of the active ingredient in the pharmaceutical composition.

CN102123697A discloses a pharmaceutical composition comprising a protein, a protease inhibitor and an absorption enhancer, wherein by adding an absorption enhancer N-(8-(2-hydroxybenzoyl)amino)octanoate (SNAC) or N- (8-(2-Hydroxybenzoyl)amino) sodium silicate (SNAD) or a combination to enhance protein absorption through the intestinal mucosal barrier; meanwhile, Steinert et al. (Am J Clin Nutr, 92: 810-817) and CN103260608A Also disclosed are pharmaceutical compositions comprising a GLP-1 analog and N-(8-(2-hydroxybenzoyl)amino)octanoic acid or a sodium salt thereof, respectively, to address the bioavailability of the GLP-1 analog in the composition. .

CN104487056A discloses a solid composition for protecting a salt of the GLP-1 analogue semaglutide and the delivery agent N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC), which composition needs to have a longer Disintegration time, in order to obtain better dissolution and oral bioavailability.

Summary of the invention

The present invention provides a pharmaceutical composition comprising a salt of an active ingredient GLP-1 receptor agonist and N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC), lactose, which has a dissolution composition Rapid and complete performance, and the preparation process of the pharmaceutical composition is simple, suitable for large-scale production; and the pharmaceutical composition has a disintegration time of 2 to 10 minutes at a total weight of 125 to 250 mg, preferably the disintegration time. For 4 to 8 minutes, the embodiment may be 4, 4.2, 4.5, 4.8, 5, 5.3, 5.5, 5.7, 6.0, 6.5, 7.0, 8.0 minutes.

The GLP-1 receptor agonist of the present invention is a GLP-1 analog, optionally comprising a substituent. A GLP-1 analogue of the invention refers to a modified peptide wherein at least one amino acid residue of the peptide is substituted with another amino acid residue, and/or at least one of the amino acid residues is deleted from the peptide, and/or wherein At least one amino acid residue is added to the peptide, and/or wherein at least one amino acid residue of the peptide is modified. This addition or deletion of amino acid residues can be carried out at the N-terminus and/or C-terminus of the peptide. In an embodiment, the GLP-1 receptor agonist comprises a substituent covalently linked to a peptide. Further, the substituents of the present invention comprise a fatty acid or a fatty diacid, and in some embodiments, the substituent comprises a C16, C18 or C20 fatty acid or a fatty diacid. In a preferred embodiment, the substituent comprises Formula X:

Wherein n is 13 to 19, for example, n is 13, 14, 15, 16, 17, 18, 19 or 20.

In some embodiments, the GLP-1 receptor agonist is a compound of Formula I or a pharmaceutically acceptable salt thereof, and the peptide of Formula I, or a pharmaceutically acceptable salt thereof, can be prepared by the method described in the Examples of CN101987868 , has the structure shown below:

In an embodiment, the active ingredient GLP-1 receptor agonist of the present invention is contained in an amount of 0.5 to 15%, and may be 0.5, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, 3.0, 3.2, 3.4, 3.6, 3.8, 4.0, 4.2, 4.4, 4.6, 4.8, 5.0, 5.2, 5.4, 5.6, 5.8, 6.0, 6.2, 6.4, 6.6, 6.8, 7.0, 7.2, 7.6, 8.0, 8.4, 8.8, 9.0, 9.4, 9.6, 10.0, 10.6, 11.0, 13, 14, 15%, preferably from 1 to 5% by weight of the pharmaceutical composition. In an embodiment of the present invention, the active ingredient is at most 10 mg by weight, and may be 0.5, 1, 2, 2.5, 3, 3.5, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8. , 8.5, 9, 9.5, 10 mg.

The NAC salt (N-(8-(2-hydroxybenzoyl)amino)octanoic acid) of the present invention may be crystalline and/or amorphous, and in embodiments, the delivery agent comprises any hydration of the NAC salt. An anhydride, a monohydrate, a dihydrate, a trihydrate or a third of a salt of a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid, in the form of a solvate or an anhydride. Monohydrate, and combinations thereof. Preferably, the delivery agent of the present invention is sodium NAC (referred to herein as "SNAC"), i.e., 8-(salicylamino)octanoate.

In an embodiment, the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid in the pharmaceutical composition of the present invention is used in an amount of 40 to 90% by weight based on the weight of the pharmaceutical composition, and may be 40, 42, or 44. 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90%, preferably 50 ~70%.

In an embodiment, the amount of SNAC in the pharmaceutical composition of the invention is at most 400 mg, preferably at most 350 mg, and may be 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 130, 140, 150, 160, 165, 170, 180, 190, 200, 210, 220, 220, 230, 240 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350 mg.

In an embodiment, the weight ratio of the active ingredient GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof and the NAC salt in the pharmaceutical composition is 1:10 or higher, that is, when measured by weight, The NAC salt is 10 times or more the active ingredient, may be 1:30 or more, or 1:60 or more, preferably 1:30, which significantly increases the in vivo bioavailability of the pharmaceutical composition.

The researchers found that the pharmaceutical composition uses microcrystalline cellulose, which has a longer disintegration time and a lower dissolution rate, whereas lactose is used, and the pharmaceutical composition has a shorter disintegration time. , faster dissolution rate and dissolution, and good oral bioavailability, in the embodiment, the amount of lactose is 10-40% by weight of the pharmaceutical composition, and may be 10, 11, 12, 13, 14 15, 15, 17, 18, 19, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40%, preferably 25 to 35%, by weight of the pharmaceutical composition. In addition or in the embodiment, water-soluble adjuvants similar in properties to lactose, such as dextrin, sucrose, and mannitol, can also be used to achieve the above effects.

In an embodiment, the pharmaceutical compositions of the present invention further comprise other pharmaceutical excipients known or determinable by those skilled in the art.

In some embodiments, the pharmaceutical compositions of the present invention further comprise a disintegrating agent known or identifiable by those skilled in the art, selected from, but not limited to, sodium starch glycolate, methylol starch. Sodium, crospovidone, croscarmellose sodium, alginic acid, alginate, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose or other cellulose derivatives, poly At least one of Klin potassium, starch or pregelatinized starch, preferably at least one of croscarmellose sodium, sodium carboxymethyl starch, low substituted hydroxypropyl cellulose or crospovidone More preferably, the disintegrant is used in an amount of 0.5 to 20% by weight of the pharmaceutical composition, and may be 0.5, 0.8, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20%, preferably 1 to 15%.

Lubricants are commonly used to facilitate processing, prevent formulation materials from adhering to production equipment, less friction between particles, improve the flow rate of the formulation, and aid in the removal of the formulation from the production equipment. In some embodiments, the pharmaceutical compositions of the present invention further comprise a lubricant, which may be selected from, but not limited to, magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, carnauba wax, hard At least one of the sodium fumarate, preferably the lubricant is used in an amount of 0.1 to 5% by weight of the pharmaceutical composition, and the examples may be 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5%, based on the weight of the pharmaceutical composition.

In an embodiment, the pharmaceutical composition of the invention contains the following ingredients:

a) 1 to 5% by weight of the active ingredient GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof,

b) 50 to 70% by weight of SNAC,

c) 25 to 35% by weight of lactose,

d) 1 to 15% by weight of a disintegrant,

e) 0.1 to 5% by weight of lubricant,

Wherein the disintegrant is selected from at least one of croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose or crospovidone; the lubricant is selected from the group consisting of hard At least one of magnesium stearate, stearic acid, palmitic acid, glyceryl behenate, calcium stearate, talc, carnauba wax, sodium stearyl fumarate; preferably, the active ingredient or The weight ratio of the pharmaceutically acceptable salt to the delivery agent SNAC is 1:30.

Further, the pharmaceutical composition of the present invention is prepared by pulverizing or pulverizing at least one of the active ingredient or a pharmaceutically acceptable salt thereof, SNAC and optionally at least one selected from the group consisting of a disintegrating agent, a filler, and a lubricant. Evenly, the uniformly mixed powder is granulated, and then granulated by granulator 2 to 3 times, and then added with additional lubricant, uniformly mixed, then compressed or filled into capsules, directly compressed or directly filled into capsules. .

In a preferred embodiment, the ratio of the amount of the lubricant added to the pharmaceutical composition of the present invention to the amount of the external lubricant is from 2:1 to 3:1 (weight ratio), and the pharmaceutical composition can be well avoided during the granulation process. The buffering phenomenon ensures particle uniformity during granulation and ensures consistency of dissolution of the active ingredient in the pharmaceutical composition with the delivery agent SNAC.

The invention also provides a pharmaceutical composition comprising the following ingredients:

a) up to 10 mg of the active ingredient of the peptide of formula I or a pharmaceutically acceptable salt thereof,

b) up to 400mg of SNAC,

c) up to 160 mg of lactose, mannitol or a combination thereof,

d) up to 50 mg of croscarmellose sodium,

e) up to 10.5 mg of magnesium stearate,

In some embodiments, the amount of active ingredient can be 0.5, 2.5, 5, 10 mg; the amount of delivery agent SNAC can be 15, 25, 35, 45, 55, 65, 75, 85, 95, 150, 200, 250 300 mg, further, the weight ratio of the active ingredient to the delivery agent SNAC is 1:30.

In a preferred embodiment, the amount of lactose is at most 160 mg, and may be 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 75, 80, 160 mg; The amount of sodium carboxymethylcellulose is at most 50 mg, preferably 20 mg, and may be 20 mg, 15 mg, 10 mg, 5 mg, 1 mg; the amount of the lubricant magnesium stearate is at most 10.5 mg, which may be 1, 1.5. 2. 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5 mg.

In a preferred embodiment, the ratio of the amount of magnesium stearate to the amount of magnesium stearate added to the pharmaceutical composition of the present invention is from 2:1 to 3:1 (weight ratio), which can well avoid the granulation process. The phenomenon of medium smashing ensures the uniformity of the granules during the granulation process and ensures the consistency of the active ingredient in the pharmaceutical composition with the delivery agent SNAC.

Factors affecting the disintegration time of the pharmaceutical composition are various, such as the influence of the tablet production process, the effect of the excipient and the main drug properties, and the storage conditions, etc., all of which can affect the disintegration time of the tablet to varying degrees, the present invention The pharmaceutical composition was obtained by the same preparation process and parameters, and the disintegration time was determined under the same conditions. In an embodiment, the pharmaceutical composition of the present invention has a disintegration time of 2 to 10 minutes at a total weight of 125 mg to 250 mg, and may be 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5. 7, 7, 7.5, 8, 8.5, 9, 9.5, 10 minutes, preferably 4 to 8 minutes.

Further, the pharmaceutical composition of the present invention may further comprise a coating agent, which may be, but not limited to, hypromellose, methyl cellulose, ethyl cellulose, methyl cellulose or hydroxy group. Propyl cellulose, polyvinyl alcohol, povidone, polyvinyl acetate resin or polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer RS and ethyl acrylate-methacrylic acid Ester copolymer dispersions, including sugar alcohol sucrose, mannitol paste, or commercially available Opadry, preferably Opadry.

The present invention also provides a method of preparing the above pharmaceutical composition, which comprises mixing an active ingredient or a pharmaceutically acceptable salt thereof with at least one selected from the group consisting of SNAC and a disintegrant, a filler, and a lubricant. 2) The mixture obtained from 1) is granulated, tableted or filled, directly compressed or directly filled.

The "by weight of the pharmaceutical composition" of the present invention is a range of values of the amount of the active ingredient or other kind of excipient used to calculate the weight of the core without the coating agent. For details, see Example 1.

Further, after the granulation step, a coating step is further included, and the coating agent used is Opadry, hypromellose, ethyl cellulose or polyvinyl alcohol, preferably Opadry.

The granulation method used in the present invention may be wet granulation and dry granulation. When the wet granulation scheme is selected, fluidized bed granulation or high shear wet granulation may be employed.

In a specific embodiment, the dry granulation process steps are as follows:

1) mixing the active ingredient or a pharmaceutically acceptable salt thereof with SNAC, lactose, a disintegrant and a part of the lubricant

Hehe,

2) After the mixed powder is subjected to dry granulation, the whole granule,

3) adding a lubricant to the granules in step 2 and mixing,

4) The mixture in step 3 is compressed into tablets.

The pharmaceutical composition of the present invention is a solid preparation, preferably a tablet, a granule, a powder (including fine granules), or a capsule. The solid preparation can be obtained by a widely known preparation method, and the maximum water content of the final dried granule after granulation is controlled to be 3% or less, and then filled into capsules or directly packaged into granules. When the dosage form is a tablet, the humidity of the tableting environment is controlled during the tableting process to ensure that the water content of the final tablet is less than 3% (3% or less), and the final composition is ensured by vacuum drying the final composition. The amount of water is less than 3%.

When the pharmaceutical composition of the present invention employs a tablet, it can be prepared by compressing the granules obtained as described above. The pressure of compression can be determined within an appropriate range. Moreover, the shape of the tablet is not particularly limited, and is preferably a lenticular shape, a disc shape, a circular shape, an elliptical shape (such as a caplet sheet), a teardrop shape or a polygonal shape (such as a triangle or a diamond shape). The prepared tablets may be coated by spraying a suspension/solution of the coating agent through a pan coater. After the coating is completed, the moisture content of the final tablet is controlled to within 3% by a drying process. The drying temperature can be selected from 40 to 80 °C. The drying method can be carried out by ordinary oven drying or vacuum drying.

When the pharmaceutical composition of the present invention employs a granule, the granules obtained as described above may be used as they are or may be granulated into a desired granule by a suitable technique. Alternatively, the granules thus prepared may be coated with a suspension of the spray coating agent with a coating agent.

The value of "related mass" of the present invention is obtained by HPLC detection.

The HPLC detection conditions of the present invention:

Column: Agilent ZORBAX 300SB-C3; detector: UV detector; detection wavelength: 220 nm; mobile phase: acidic aqueous solution / acetonitrile.

The dissolution rate of the pharmaceutical composition of the present invention is determined according to the second method (paddle method) of the dissolution test of the Chinese Pharmacopoeia 2015 edition four-part general rule 0931, using 0.1% Tween 80 pH 6.8 phosphate buffer as the dissolution medium, preferably 500 ml. 0.1% Tween 80 pH 6.8 phosphate buffer, and the dissolution test of the composition of the invention at 37 ± 0.5 ° C at a paddle speed of 50 rpm; in an embodiment, the pharmaceutical composition of the invention has a dissolution greater than 45 minutes. Equal to 90%, may be greater than or equal to 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100%, with good dissolution rate and dissolution.

Further, in an embodiment, the pharmaceutical composition of the present invention has a dissolution degree of 80% or more in 15 minutes, and may be greater than or equal to 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90. 91, 92, 93, 94, 95, 96, 97, 98, 99, 100%.

The pharmaceutical composition disintegration test of the present invention: a disintegration test was carried out using a Tianda Tianfa Disintegration Tester. Set the time limit inspection method based on the Chinese Pharmacopoeia's four general rules 0921. The GL tablets were placed in a basket using a lift disintegrator, and the basket was immersed in 800 ml of purified water maintained at 37 ° C in a 1 L beaker. The time to complete disintegration was measured. In addition, the surface erosion behavior of the tablets was visually observed during the disintegration test.

The GLP-1 analog of the present invention provides a peptide of the formula I which belongs to the amphoteric compound. Those skilled in the art can react with the acidic or basic compound to form a salt by a known technique. The acid which is usually used to form the acid addition salt is: Hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid; salts including sulfates, Pyrosulfate, trifluoroacetate, sulfite, bisulfite, phosphate, hydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, hydrochloride, bromide, iodide, B Acid salt, propionate, octoate, acrylate, formate, isobutyrate, hexanoate, heptanoate, propiolate, oxalate, malonate, succinate, Suberate, fumarate, maleate, butyne-1,4-diate, hexyne-1,6-diate, benzoate, chlorobenzoate, methyl Benzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phenylacetate, phenylpropionate, phenylbutyrate, lemon Salt, lactate, γ-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalenesulfonate, naphthalene-2-sulfonate, mandelate Etc., preferably a trifluoroacetate salt. Alkaline substances can also form salts with GLP-1 analogues, including ammonium, alkali metal or alkaline earth metal hydroxides, as well as carbonates, hydrogencarbonates, typically sodium hydroxide, potassium hydroxide. , ammonium hydroxide, sodium carbonate, potassium carbonate, etc.

The delivery agent of the present invention can be prepared, for example, by the methods described in WO 96/030036, WO 00/046182, WO 01/092206 or WO 2008/028859, or obtained commercially; the active ingredient of the present invention may be a peptide of the formula I or Pharmaceutically acceptable salts can be obtained by the methods described in CN101987868A. The pharmaceutical excipients used in the present invention are commercially available, such as lactose and the like.

DRAWINGS

Figure 1: Dissolution profiles of Examples 1-3 in 0.1% Tween 80 pH 6.8 phosphate buffer;

Figure 2: Dissolution profiles of Examples 4-6 in 0.1% Tween 80 pH 6.8 phosphate buffer;

Figure 3: Dissolution profiles of Examples 5, 7-8 in 0.1% Tween 80 pH 6.8 phosphate buffer;

Figure 4: Dissolution profiles of Examples 8-10 in 0.1% Tween 80 pH 6.8 phosphate buffer.

detailed description

The invention is further illustrated in detail by the following examples and experimental examples. The examples and the examples are for illustrative purposes only and are not intended to limit the scope of the invention.

Examples 1-3

The peptide represented by Formula I (hereinafter referred to as Compound A), SNAC, lactose or microcrystalline cellulose, croscarmellose sodium, povidone K30, and magnesium stearate were dry-processed according to the ratio in Table 1. The granules are treated, then the dry granules are dry granulated, and a prescribed amount of magnesium stearate is added and mixed well. The resulting total mixed granules were compressed into tablets.

Table 1

Experimental Example 1: Disintegration experiment

When the microcrystalline cellulose is selected as the filler in the first embodiment, during the preparation of the granules, the granule powder is less, and the tablet disintegrates slowly; in the embodiment 2, the filler is lactose, and the lactose is a water-soluble auxiliary material, during preparation. The particles are relatively uniform and disintegrate faster; in the preparation process, the particle state is good in the preparation process, and the disintegration time is shortened after preparation into a tablet.

Experimental Example 2: Dissolution experiment

The dissolution rate of the tablets of Examples 1 to 3 was measured according to the second method (paddle method) of the dissolution test of the Chinese Pharmacopoeia 2015 edition of the general rules of the 0931 method. 500 ml of 0.1% Tween 80 pH 6.8 phosphate buffer was used as the dissolution medium, and the dissolution test was carried out at 37 ± 0.5 ° C at a paddle speed of 50 rpm. The results showed that in Example 1, the dissolution of Compound A was incomplete and was inconsistent with the dissolution of SNAC. In Examples 2 to 3, the compound A was completely eluted and was consistent with the dissolution of SNAC. The dissolution data is shown in Table 2.

Table 2

Examples 4-7

Compound A, SNAC, lactose, croscarmellose sodium or crospovidone, low-substituted hydroxypropylcellulose, magnesium stearate are subjected to dry granulation according to the ratio in Table 3, and then The dry granules are dried and granulated, and a prescribed amount of magnesium stearate is added and mixed well. The resulting total mixed granules were compressed into tablets.

table 3

Experimental Example 3: Disintegration experiment

In Examples 4 to 6, croscarmellose sodium and crospovidone were used as disintegrants, and the tablet disintegrated faster; in Example 7, low-substituted hydroxypropylcellulose was used as a disintegrating agent. The disintegration time has increased.

Experimental Example 4: Dissolution experiment

The dissolution rate of the tablets of Examples 4 to 6 was measured according to the second method (paddle method) of the dissolution test of the Chinese Pharmacopoeia 2015 edition four general rules 0931. 500 ml of 0.1% Tween 80 pH 6.8 phosphate buffer was used as the dissolution medium, and the dissolution test was carried out at 37 ± 0.5 ° C at a paddle speed of 50 rpm. The results showed that in Example 5, Compound A was completely eluted. In Examples 4 and 6, the dissolution rate of Compound A was slower than that in Example 5, and the final dissolution was not complete in Example 5. The dissolution data is shown in Table 4.

Table 4

Examples 8-9

Compound A, SNAC, lactose, croscarmellose sodium, magnesium stearate were subjected to dry granulation treatment according to the ratio in Table 5, and then dry granules were dry granulated, and a prescribed amount of stearic acid was added. Magnesium, mixed evenly. The resulting total mixed granules were compressed into tablets. In the embodiment 8, the sample granule is easily adhered during the dry granulation process, which is disadvantageous for particle collection; in the embodiment 9, in the dry granulation process, the particles are uniform, there is no phenomenon of sticking the sample groove, and the particle has good fluidity, and the tablet is compressed. There is no overshoot in the process.

table 5

Experimental Example 5: Dissolution experiment

The dissolution rate of the tablets of Examples 8 to 9 was measured according to the second method (paddle method) of the dissolution test of the Chinese Pharmacopoeia 2015 edition four general rules 0931. 500 ml of 0.1% Tween 80 pH 6.8 phosphate buffer was used as the dissolution medium, and the dissolution test was carried out at 37 ± 0.5 ° C at a paddle speed of 50 rpm. The results showed that in Examples 8-9, the particle uniformity was better at the time of granulation, the smear phenomenon was lighter, and the dissolution of Compound A and SNAC was better. The dissolution data is shown in Table 6.

Table 6

Experimental Example 6: In vivo bioavailability

Animal administration, blood sampling: The study used cynomolgus monkeys, randomly divided into 6 groups, male and female. A certain amount of the pharmaceutical composition is administered by gavage. Blood samples were taken at the following time points: 0 h before administration, 5 min, 15 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 10 h, 24 h after administration.

Plasma treatment: Collect whole blood into a centrifuge tube containing anticoagulant, store in an ice bath, centrifuge at 2 to 8 ° C, centrifuge at 3500 rpm / min, and centrifuge for 10 min. The collected plasma was divided into 2 portions and stored in an additionally labeled EP tube at -70 ± 10 ° C until the sample was analyzed.

Data Analysis: Blood samples were analyzed by bioanalytical researchers using LC-MS/MS methods to determine the concentrations of Compound A and SNAC in biological samples, and the bioanalytical data were analyzed by pharmacokinetics.

The bioavailability of the formulation of Example 1 relative to subcutaneous was 0.25%, the bioavailability of the formulation of Example 3 relative to subcutaneous was 0.36%, and the bioavailability of the formulation of Example 9 relative to the subcutaneous was 0.68%.

Examples 10 to 11

Compound A, SNAC, lactose, croscarmellose sodium, magnesium stearate were subjected to dry granulation according to the ratio in Table 7, and then the dry granules were dry granulated, and a prescribed amount of stearic acid was added. Magnesium, mixed evenly. The resulting total mixed granules were compressed into tablets.

Table 7

Experimental Example 7: Dissolution experiment

The dissolution rate of the tablets of Examples 10 to 11 was measured according to the second method (paddle method) of the dissolution test of the Chinese Pharmacopoeia 2015 edition four general rules 0931. 500 ml of 0.1% Tween 80 pH 6.8 phosphate buffer was used as the dissolution medium, and the dissolution test was carried out at 37 ± 0.5 ° C at a paddle speed of 50 rpm. The results showed that in Examples 10 to 11, Compound A was completely eluted and was consistent with the dissolution of SNAC. The dissolution data is shown in Table 8.

Table 8

Experimental Example 8: Stability data:

The tablets of Example 9 and Example 10 were allowed to stand under accelerated conditions (40 ° C, RH 75%) for 3 months, and the product quality was stable.

Table 9

Claims (15)

A pharmaceutical composition comprising an active ingredient GLP-1 receptor agonist, a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC), and lactose, preferably the amount of the NAC salt is in the form of a drug 40 to 90%, more preferably 50 to 70% by weight of the composition; and the GLP-1 agonist optionally comprises a substituent, preferably the substituent comprises Formula X,

Where n is 13 to 19. The pharmaceutical composition according to claim 1, characterized in that the active ingredient is present in an amount of from 0.5 to 15%, preferably from 1 to 5%, based on the weight of the pharmaceutical composition. The pharmaceutical composition according to claim 1 or 2, characterized in that the NAC salt is NAC monosodium (SNAC). The pharmaceutical composition according to claim 1 or 2, wherein the weight ratio of the active ingredient to the SNAC in the pharmaceutical composition is from 1:10 to 1:60, preferably 1:30. The pharmaceutical composition according to any one of claims 1 to 4, characterized in that the amount of the GLP-1 receptor agonist is at most 10 mg, preferably at most 5 mg. The pharmaceutical composition according to any one of claims 1 to 5, wherein the amount of the N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC) salt is at most 400 mg. The pharmaceutical composition according to any one of claims 1 to 6, wherein the GLP-1 receptor agonist has a peptide of the formula I or a pharmaceutically acceptable salt thereof:

The pharmaceutical composition according to any one of claims 1 to 7, wherein the pharmaceutical composition further contains a disintegrating agent selected from the group consisting of croscarmellose sodium and carboxymethyl starch. At least one of sodium, low-substituted hydroxypropylcellulose or crospovidone is preferably used in an amount of from 0.5 to 20% by weight, preferably from 1 to 15% by weight based on the total mass of the pharmaceutical composition. The pharmaceutical composition according to any one of claims 1-8, characterized in that the amount of the lactose is from 10 to 40% by weight, more preferably from 25 to 35% by weight based on the weight of the pharmaceutical composition. The pharmaceutical composition according to any one of claims 1 to 9, wherein the pharmaceutical composition further contains a lubricant selected from the group consisting of magnesium stearate, stearic acid, palmitic acid, and behenic acid. At least one of glycerin, calcium stearate, talc, carnauba wax, and sodium stearyl fumarate is preferably used in an amount of from 0.1 to 5% by weight based on the weight of the pharmaceutical composition. A pharmaceutical composition according to any one of claims 1 to 10 comprising the following ingredients: a) 1 to 5% by weight of the active ingredient GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof, b) 50 to 70% by weight of SNAC, c) 25 to 35% by weight of lactose, d) 1 to 15% by weight of a disintegrant selected from at least croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose or crospovidone One kind, e) 0.1 to 5% by weight of a lubricant selected from the group consisting of magnesium stearate, stearic acid, palmitic acid, glyceryl behenate, calcium stearate, talc, carnauba wax, and hard fat At least one of sodium salt. A pharmaceutical composition comprising the following ingredients: a) up to 10 mg of the active ingredient of the peptide of formula I or a pharmaceutically acceptable salt thereof, b) up to 400mg of SNAC, c) up to 160 mg of lactose, mannitol or a combination thereof, d) up to 50 mg of croscarmellose sodium, e) up to 10.5 mg of magnesium stearate,

The pharmaceutical composition according to claim 11, wherein the pharmaceutical composition is respectively obtained from at least one of an active ingredient GLP-1 receptor agonist, SNAC, lactose, and optionally selected from a disintegrant and a lubricant. After pulverizing or sifting through 30~50 mesh sieve, mix evenly, then make the mixed powder into granules, then add granules after 2~3 times of granulating machine, add extra lubricant, mix well and then compress or fill the capsules. Made by direct compression or direct filling of capsules. The pharmaceutical composition according to any one of claims 1 to 13, which has a disintegration time of 2 to 10 minutes at a total weight of 125 to 250 mg, preferably 4 to 8 minutes. A method of preparing the pharmaceutical composition according to any one of claims 1 to 14, comprising: 1) at least one of the active ingredient or a pharmaceutically acceptable salt thereof, SNAC, lactose, and optionally selected from the group consisting of a disintegrant and a lubricant Mixing, 2) granulation of the mixture obtained from 1), tableting or filling capsules, direct compression or direct filling of the capsules.

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