WO2024017139A1 - Pharmaceutical composition containing glp-1 receptor agonist analog - Google Patents

Abstract

The present invention provides a pharmaceutical composition, comprising a GLP-I receptor agonist or an analog thereof, and further comprising one or more of the following components: a pro-penetrating agent, a basic substance, and an adhesive material. The technology can not only greatly improve the bioavailability and solve the problem of a low response rate for patients, but also is expected to solve the problem of low administration compliance of previous marketed medicines; and the prescription process is simple and stable, and production and transportation are convenient.

Description

A pharmaceutical composition containing a GLP-1 receptor agonist analog Technical field

The invention belongs to the field of medicine.

Background technique

There are currently many patients with diabetes in the world. The International Diabetes Federation has announced that it is expected to reach 629 million people in 2045, and the majority of patients have type Ⅱ diabetes. GLP-1 receptor agonist analogs such as semaglutide and liraglutide have good hypoglycemic effects on type 2 diabetes and can significantly reduce the risk of major cardiovascular events (MACE) in patients with type 2 diabetes. Therefore, GLP-1 analogues can better benefit diabetic patients. In addition, some GLP-1 analogues have been approved for weight loss.

However, because GLP-1 analogue drugs often have characteristics such as large molecular weight and easy degradation in the gastrointestinal tract, it is difficult to achieve effective bioavailability through the oral route. Therefore, the mainstream method of administration in the market is injection. In 2019, Novo Nordisk launched the oral administration of the GLP-1 agonist analog semaglutide for the first time, but its oral bioavailability is also extremely low, less than 1%, so the market price is not beneficial to patients. friendly.

Contents of the invention

Based on the above problems, the present invention intends to adopt new formulation technology to improve the oral bioavailability of GLP-1 receptor agonists or their analogues, in order to reduce the usage of API under the same curative effect, reduce the cost of medication for patients, and at the same time reduce the risk of diabetes. the social burden it brings.

Specifically, the present invention provides a pharmaceutical composition, which includes a GLP-I receptor agonist or an analog thereof, and one or more of the following components: a penetration enhancer, an alkaline substance, and an adhesive material.

Wherein, the composition includes one of the following combinations:

A. Including GLP-I receptor agonists or their analogs, penetration enhancers; further, adhesive materials or alkaline substances;

B. Including GLP-I receptor agonists or their analogues, adhesive materials; further, also includes penetration enhancers or alkaline substances;

C. Including GLP-I receptor agonists or analogs thereof, and alkaline substances; further, it also includes penetration enhancers or adhesive materials.

The alkaline substances mentioned in the present invention refer to additional alkaline substances other than the penetration enhancer. Alkaline substances are key components in the present invention and have a significant impact on improving bioavailability.

Wherein, the composition includes one of the following combinations:

a. Including GLP-I receptor agonists or analogs thereof, penetration enhancers, and alkaline substances;

b. Including GLP-I receptor agonists or analogs thereof, penetration enhancers, and adhesive materials;

c. Including GLP-I receptor agonists or their analogs, alkaline substances, and adhesive materials.

Wherein, the mass ratio of GLP-I receptor agonist or its analog: penetration enhancer is 1:15-40, which can be selected from 1:15, 1:16, 1:17...1:37 , 1:38, 1:39, 1:40, etc.

Wherein, the mass ratio of GLP-I receptor agonist or its analog: alkaline substance is 1:1-15, which can be selected from 1:1, 3:5, 1:2, 1:3, 1:4. .....1:11, 1:12, 1:13, 1:14, 1:15, etc.

Wherein, the mass ratio of GLP-I receptor agonist or its analog: adhesive material is 1:0.5-10, which can be selected from 1:0.5, 1:1, 3:5, 1:2, 1:3, ......1:7, 1:8, 1:9, 1:10, etc.

Wherein, the GLP-1 analog includes one or more of exenatide, liraglutide, linasitide, albiglutide, semaglutide, and dulaglutide.

Wherein, the penetration enhancer is selected from one of nonionic surfactants, fatty acid salts, calcium ion chelating agents, and cholate surfactants.

Wherein, the nonionic surfactant includes sodium lauryl sulfate and Tween 80; the fatty acid salt includes sodium caprate, sodium N-(8-(2-hydroxybenzoyl)amino)octanoate (SNAC ); the calcium ion chelating agent includes EDTA and carbomer; the cholate surfactant includes sodium chenodeoxycholate, sodium glycocholate, and sodium taurocholate.

The alkaline substance may include an organic base or an inorganic base.

Wherein, the alkaline substances include sodium carbonate, sodium bicarbonate, sodium acetate, disodium hydrogen phosphate, sodium phosphate, dipotassium hydrogen phosphate, aluminum hydroxide, sodium glycinate, sodium glycocholate, arginine, lysine One or more of acid, histidine, and magnesium oxide.

Wherein, the adhesive material includes one or more of natural polymer materials and synthetic polymer materials.

Wherein, the natural polymer materials include gelatin, pectin, gum arabic, and sodium alginate; the synthetic polymer materials include polyacrylic acid (Polycarbo phil), carboxymethylcellulose sodium (CMC-Na), hydroxypropyl Methyl cellulose (HPMC), hydroxyethyl cellulose (HPC), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG).

Wherein, the composition further includes one or more of a lubricant, a plasticizer, a coating material, an anti-sticking agent, and an opacifying agent.

Wherein, the composition is a solid preparation.

Wherein, the solid preparations include tablets, pills, and capsules.

Among them, the mass ratio is selected from one of the following:

Side 1:

Side 2:

Square 3:

Square 4:

Wherein, the lubricant includes magnesium stearate, micronized silica gel, and talc powder.

The present invention also provides a preparation method for the above pharmaceutical composition, which includes the following contents: SNAC is mixed with lubricant and tableted, and mixed with other components for tableting.

The solid composition can be presented in the form of microtablets or pellets, and its release time can be controlled to allow the API and SNAC to be released completely in a shorter time, such as within 30 minutes, which can achieve more absorbable parts and unit time. Include higher concentrations of SNAC and API for better absorption.

The solid composition microtablets can be pressed into different hardnesses to meet the requirements of different dissolution times for multiple tablets.

Description of drawings

Figure 1 Drug time curve in rats

Figure 2 Medication time curve chart in beagle dogs

Detailed ways

An implementation example takes semaglutide as an example.

Example 1

This embodiment includes a pharmaceutical composition containing semaglutide. The proportions of each component in the composition include the following components based on mass fraction:

The preparation method provided in this embodiment is as follows:

Dry tablet SNAC and magnesium stearate, then grind the tablets through a 65-mesh screen, and then tablet together with semaglutide, povidone, sodium carbonate, and magnesium stearate, using a 2.5-diameter Millimeter (2.5mm) die to compress 15mg microtablets.

Example 2

This embodiment includes a pharmaceutical composition containing semaglutide. The proportions of each component in the composition include the following components based on mass fraction:

The preparation method provided in this embodiment is as follows:

Dry tablet SNAC and magnesium stearate, then grind the tablets through a 65-mesh screen, and then tablet together with semaglutide, povidone, sodium carbonate, and magnesium stearate, using a 2.5-diameter Millimeter (2.5 mm) die to compress 30 mg microtablets.

Example 3

This embodiment includes a pharmaceutical composition containing semaglutide. The proportions of each component in the composition include the following components based on mass fraction:

The preparation method provided in this embodiment is as follows:

Dry tablet SNAC and magnesium stearate, grind the tablets through a 65-mesh screen, and then tablet together with semaglutide, povidone, magnesium oxide, and magnesium stearate, using a 2.5-diameter Millimeter (2.5 mm) die to compress 30 mg microtablets.

Example 4

This embodiment includes a pharmaceutical composition containing semaglutide. The proportions of each component in the composition include the following components based on mass fraction:

The preparation method provided in this embodiment is as follows:

Dry tablet SNAC and magnesium stearate, grind the tablets through a 65-mesh screen, and then tablet together with semaglutide, povidone, sodium bicarbonate, and magnesium stearate. A 2.5mm (2.5mm) die presses 30mg microtablets.

Example 5

This embodiment includes a pharmaceutical composition containing semaglutide. The proportions of each component in the composition include the following components based on mass fraction:

The preparation method provided in this embodiment is as follows:

Dry tablet SNAC and magnesium stearate, then grind the tablets through a 65 mesh screen, and then tablet together with semaglutide, povidone, magnesium oxide, sodium carbonate, and magnesium stearate, using A 2.5 mm diameter die presses 10 mg microtablets to fill the capsules.

Example 6

This embodiment includes a pharmaceutical composition containing semaglutide. The proportions of each component in the composition include the following components based on mass fraction:

The preparation method provided in this embodiment is as follows:

Compress semaglutide, SNAC, povidone, sodium acetate, and magnesium stearate together into 30 mg microtablets using a die with a diameter of 2.5 mm.

Example 7

This embodiment includes a pharmaceutical composition containing semaglutide. The proportions of each component in the composition include the following components based on mass fraction:

The preparation method provided in this embodiment is as follows:

Dry tablet SNAC and magnesium stearate, then grind the tablets through a 65-mesh screen, and then tablet together with semaglutide, povidone, dipotassium hydrogen phosphate, and magnesium stearate. Use the diameter 30 mg microtablets are pressed for a 2.5 mm (2.5 mm) die.

Example 8

This embodiment includes a pharmaceutical composition containing semaglutide. The proportions of each component in the composition include the following components based on mass fraction:

The preparation method provided in this embodiment is as follows:

Dry tablet SNAC and magnesium stearate, grind the tablets through a 65-mesh screen, and then tablet together with semaglutide, povidone, Tween 80, and magnesium stearate. A 2.5mm (2.5mm) die presses 15mg microtablets.

Example 9

This embodiment includes a pharmaceutical composition containing semaglutide. The proportions of each component in the composition include the following components based on mass fraction:

The preparation method provided in this embodiment is as follows:

Dry tablet SNAC and magnesium stearate, grind the tablets through a 65-mesh screen, and then tablet together with semaglutide, SNAC, povidone, sodium carbonate, and magnesium stearate. Use the diameter Compress 15 mg microtablets using a 2.5 mm (2.5 mm) (a) die or 360 mg tablets using a 10 mm (10 mm) diameter disc (b).

Example 10

This embodiment includes a pharmaceutical composition containing semaglutide. The proportions of each component in the composition include the following components based on mass fraction:

The preparation method provided in this embodiment is as follows:

Prepare API, part of SNAC, HPMC, and talc with water to form a suspension. Use fluidized bed coating. Spray the prepared suspension containing API onto the core of the pill as the first layer of coating, and then apply part of SNAC. , HPMC, sodium carbonate, and talcum powder are prepared into a suspension with water, and continue to be coated with fluidized bed as the second layer of coating. Finally, a titanium dioxide coating liquid is prepared as a sunscreen agent.

Examine the relevant evaluation indicators in vitro of the pharmaceutical compositions according to the embodiments of the present invention.

Test Example 1 Hardness and Tablet Disintegration

The formulation compositions of the examples were pressed into tablets of different hardness, and the hardness of the tablets was measured using Pharma Test (33AA02), that is, the force necessary to break the tablets was measured. This test was based on the pharmacopoeia method Ph Eur 2.9.8.

The disintegration time can be measured using a conventional disintegration tester according to the pharmacopoeia method. The disintegrator consists of a basket containing multiple plastic tubes with top and bottom openings, the bottom of which is covered by a screen. The tablets are placed in a plastic tube and a disk for automatic disintegration detection is placed above the tablets. In a 1 L beaker, the basket was immersed in 800 ml of purified water maintained at 37°C, and the time for complete disintegration was measured. Furthermore, the surface erosion behavior of the tablets could be visually observed during the disintegration test.

Table 1

According to the tablet dissolution time, the tablet (a) of Example 9 has the shortest disintegration time and the fastest dissolution time. The tablets are now administered in the stomach on an empty stomach, because the dissolution time of the tablets is the shortest, the interval between meals can be shortened, and the tablets can be released quickly, which is more conducive to the absorption of the active ingredients.

Dissolution study of tablets

The analysis was performed based on pharmacopoeial method Ph Eur 2.9.3, Apparatus 2 (paddle apparatus). Use a 250ml mini container with a mini paddle at 20rpm. The dissolution medium used for the dissolution testing was 100 ml of 200 mM KH2PO4 (containing 0.5% BRIJ35 to avoid GLP-1 agonist sticking to the container walls or paddle), pH 6.8. Samples were taken after 5, 15, 30, 45, 60, 120 and 130 minutes. Take a sample volume of 5 ml and use a syringe to take the sample. After each sampling, the same volume (5 ml) of dissolution medium was added to the container to keep the total volume constant at 100 ml. Press the sample through 0.22μm -GV filter membrane. Finally, the sample API concentration and delivery agent concentration were analyzed by HPLC.

Dissolution sample conditions: 11 tablets were administered in Example 1, Example 8, and Implementation 9(a), and 1 tablet was administered in Example 9(b).

Table 2

Test Example 2 In vivo pharmacokinetic study - pharmacokinetic experiment in rats

Sample information for testing:

table 3

Experimental program:

SD adult male rats were randomly divided into three groups, with a body weight of 250g±20g during the study period. They were fasted for 10 hours before the experiment, administered a single dose on an empty stomach, and fed 4 hours after administration; blood collection time point: 0 , 0.25, 0.5, 1, 2, 4, 6, 8h, 24h. The HPLC/MS-MS method was used to measure the plasma drug concentration of API in vivo for 8 hours, and DAS software was used to calculate the pharmacokinetic parameters of API in vivo. The original Rybelsus tablets are divided into 1 mg dose for rats, and each rat is given approximately 30 mg in total.

The pharmacokinetic parameters of Rybelsus and Examples experimentally obtained in rats are as follows:

Table 4

Among them, Tmax is the peak time, Cmax is the maximum blood concentration, and AUC(0-t) is the AUC of the duration from the beginning of administration to the last blood collection point, that is, the area of the drug curve.

It can be seen from the above table that the exposure amounts of Examples 1, 2, and 4 in rats are higher than that of Rybelsus, and the bioavailability is increased to 6.4 times.

Rybelsus and Examples 1, 5, 8, and 9 in rats, the drug time curve is shown in Figure 1.

Test Example 3 In vivo pharmacokinetics study - canine pharmacokinetics experiment

Sample information for testing:

table 5

Experimental program:

6 male beagle dogs were randomly divided into 3 groups, with 2 dogs in each group, weighing about 5kg during the study period. They were fasted for 12 hours before the experiment and water was deprived of water 1 hour before administration; intramuscular injection was given 30 minutes before administration. All experimental animals received 6 μg/kg of pentagastrin. The administration method was a single intragastric administration, and all experimental animals were given 20 mL of acidified water with pH 1.2 immediately after the administration. Water and food were restored 30 minutes after administration. Blood collection time points: 0, 0.167, 0.5, 1, 2, 4, 8, 24, 48, 72, 96, 120, 144, 168h. The HPLC/MS-MS method was used to measure the plasma drug concentration of API in vivo for 168 hours, and DAS software was used to calculate the pharmacokinetic parameters of API in vivo.

The pharmacokinetic parameters of Rybelsus and Examples experimentally obtained in beagle dogs are as follows:

Among them, Tmax is the peak time, Cmax is the maximum blood concentration, and AUC(0-t) is the time from the beginning of administration to the last blood collection.

The AUC of the duration of the point is the area of the drug curve.

It can be seen from the above table that the exposure of Examples 1 and 9 in beagle dogs is higher than that of Rybelsus, and the bioavailability is increased several times.

The drug-time curve of Rybelsus and Examples 1 and 9 in beagle dogs is shown in Figure 2.

The existing technology may have insufficient bioavailability, low drug compliance, or may be ineffective for individual patients. etc., cannot effectively solve various problems of its commercialization. This technology can not only improve bioavailability and solve the problem of low patient effectiveness, but also is expected to solve the problem of low medication compliance of first-to-market drugs. The prescription process is simple and stable, and facilitates production and transportation.

Claims (12)

A pharmaceutical composition, which includes a GLP-I receptor agonist or an analog thereof, characterized in that it also includes an alkaline substance; the alkaline substance may include an organic base or an inorganic base; a GLP-I receptor agonist Or its analogue: the mass ratio of the alkaline substance is 1:1-15; further, the mass ratio is selected from 1:1-10, furthermore, selected from 1:2-10. The pharmaceutical composition according to claim 1, characterized in that: the GLP-1 analogues include exenatide, liraglutide, linasitide, albiglutide, semaglutide, doxepin One or more laglutide; the alkaline substances include sodium carbonate, sodium bicarbonate, sodium acetate, disodium hydrogen phosphate, sodium phosphate, dipotassium hydrogen phosphate, aluminum hydroxide, sodium glycinate, and sodium glycocholate , one or more of arginine, lysine, histidine, and magnesium oxide. The pharmaceutical composition according to claim 1, characterized in that: it also includes a penetration enhancer or an adhesive material; the mass ratio of GLP-I receptor agonist or its analog: the adhesive material is 1:0.5-10; The mass ratio of GLP-I receptor agonist or its analog: penetration enhancer is 1:5 to 100. The pharmaceutical composition according to claim 3, characterized in that: the mass ratio of GLP-I receptor agonist or analog thereof: penetration enhancer is selected from 1:15-50; further, the mass ratio is 1: 20-30; The mass ratio of GLP-I receptor agonist or analog thereof:adhesive material is selected from 1:1-10. The pharmaceutical composition according to claim 3, characterized in that: the penetration enhancer is selected from one of nonionic surfactants, fatty acid salts, calcium ion chelating agents, and cholates; The adhesive material includes one or more of natural polymer materials and synthetic polymer materials. The pharmaceutical composition according to claim 5, characterized in that: the nonionic surfactant includes sodium lauryl sulfate, Tween 80; the fatty acid salt includes sodium decanoate, N-(8-( Sodium 2-hydroxybenzoyl)amino)octanoate (SNAC); the calcium ion chelating agent includes EDTA, carbomer; the cholic acid salts include sodium chenodeoxycholate, sodium glycocholate, and taurine sodium acid; The natural polymer materials include gelatin, pectin, gum arabic, and sodium alginate; the synthetic polymer materials include polyacrylic acid (Polycarbo phil), carboxymethylcellulose sodium (CMC-Na), hydroxypropylmethane cellulose (HPMC), hydroxyethyl cellulose (HPC), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG). The pharmaceutical composition according to claim 1, characterized in that: the composition further includes a surfactant; further, the surfactant includes Tween, polyoxyethylene (40), hydrogenated castor oil (RH40), Caprylic and capric acid polyethylene glycol glycerides (labrasol). The pharmaceutical composition according to claim 1, characterized in that: the composition further includes one or more of a lubricant, a plasticizer, a coating material, an anti-adhesive agent, and an opacifying agent. The pharmaceutical composition according to claim 1, characterized in that: the composition is a solid preparation; further, the solid preparation includes tablets, pills, and capsules. The pharmaceutical composition according to claim 1, characterized in that: its mass ratio is selected from the following one: Side 1:
Side 2:

Square 3:
Square 4:
The pharmaceutical composition according to claim 8, wherein the lubricant includes magnesium stearate, micronized silica gel, and talc. The preparation method of tablets according to claim 9, characterized in that: it includes the following contents: SNAC is mixed with lubricants and tableted with other ingredients.