CN119317635A

CN119317635A - Reusable, multi-dose, variable-dose, single-use pen-injector for type 2 diabetes and weight management

Info

Publication number: CN119317635A
Application number: CN202380044831.6A
Authority: CN
Inventors: 穆泰延·埃萨基穆图·卡纳安; 德布贾尼·马诺耶·辛格; 图沙尔·苏拉杰马尔·那霸; 约格什·科达·瓦格; 沙鲁巴·库马尔
Original assignee: Zadusi Life Sciences Co ltd
Current assignee: Zadusi Life Sciences Co ltd
Priority date: 2022-06-08
Filing date: 2023-06-06
Publication date: 2025-01-14
Also published as: EP4536691A1; WO2023238017A1; MX2024015194A; AU2023285400A1

Abstract

It is an object of the present invention to provide a liquid composition of semaglutin having phenol at a concentration of 0.11% w/w to 0.5% w/w which will enhance the stability of the composition. The invention also provides a method for preparing the composition of the semaglutin and a method for treating diabetes and obesity by using the composition.

Description

Reusable multi-dose variable dose single pen injector for type 2 diabetes and weight management

Technical Field

The present invention relates to a pharmaceutical composition of semaglutin (Semaglutide) delivered by a reusable pen-type injector device. In one embodiment, the pen injector device comprises one or more cartridges adapted to deliver multiple doses and different variable doses of semaglutin for the treatment of type 2 diabetes and weight management. The invention also relates to a novel liquid pharmaceutical composition comprising semaglutin at a concentration of 3mg/mL to 25mg/mL and phenol at a concentration of 0.11% w/w to 0.5% w/w.

Background

Semaglutin is one of the effective drugs for treating type 2 diabetes and weight management. The medicine is prepared into oral and injection dosage forms.

WO2006097537 discloses for the first time semaglutin. The same document also discloses certain injectable compositions of semaglutin.

Semaglutin is a long-acting human glucagon-like peptide-1 analog, i.e., aib ⁸,Arg³⁴ -GLP-1 (7-37) analog, substituted on the epsilon-lysyl group of the lysine residue at position 26 with the (S) -22, 40-dicarboxy-10,19,24-trioxo-3,6,12,15-tetraoxa-9,18,23-triaza-tetrahydride-1-acyl side chain. The side chain consists of two 8-amino-3, 6-dioxaoctanoic Acid (ADO) spacers, one gamma-glutamic acid (Glu) spacer and one fatty diacid (1, 18-octadecanedioic acid). Pharmaceutical dosage forms comprising semaglutin are disclosed in WO2006097537 and WO 2019038412. There are two approved brands of semaglutin injection, namelyAnd。

Is approved for the treatment of diabetes and is available in disposable pen injectors and different devices (device 1:0.25mg, 0.5mg; device 2:1mg; device 3:2 mg) are used according to the different doses.The phenol concentration was 5.5mg/ml as a subcutaneous injection solution.

Provided as a clear, colorless subcutaneous injection solution, was loaded into a 1mL pre-filled type I glass syringe (PFS) equipped with a stainless steel needle, a rigid needle shield (type II/polyisoprene) and a rubber plunger (type I/chlorobutyl rubber). The PFS is assembled in a disposable (single use) pre-filled pen (PFP).Each of the packages was used in 4 PFP, and each of the packages contained 0.25mg of semaglutin (content: strategth) in 0.5mL, 0.5mg of semaglutin (content: 0.5 mg) in 0.5mL, 1mg of semaglutin (content: 1 mg) in 0.5mL, 1.7mg of semaglutin (content: 1.7 mg) in 0.75mL, and 2.4mg of semaglutin (content: 2.4 mg) in 0.75 mL.

Approved injectionOne of the major drawbacks of the semaglutin formulation is that the injection formulation is either provided in a single-use single-pen syringe or in a fixed-dose, multi-dose syringe. Thus, the patient needs to use/purchase a disposable pen weekly, or to purchase a different pen injector for different doses throughout the treatment cycle according to an approved dosage regimen. The pen provided for injection is a disposable pen, which should be discarded after each administration. This not only increases the cost of treatment for the patient, but also creates unnecessary waste and environmental impact.

Furthermore, as explained in WO2019038412, when higher amounts of phenol are used to formulate higher doses of semaglutin required for weight management treatment, the semaglutin liquid formulation is unstable. Thus, WO'412 discloses semaglutin formulations that do not contain phenol or contain negligible amounts of phenol. Such typical semaglutin formulations are likely to necessitate the use of a disposable pen when used for drug delivery.

Thus, there is a need to study and develop a new semaglutin formulation that is more cost-effective to the patient, stable enough to avoid delivery with a disposable pen (single use pen), provides better patient compliance, and is environmentally friendly. The inventors of the present invention have surprisingly found that by optimizing the concentration of phenol in the formulation it is possible to formulate higher concentrations of semaglutin without affecting its stability. With such a stable formulation, multiple doses of semaglutin can be delivered using a multi-dose syringe device containing a cartridge (cartridge), and the device can be reused by replacing the cartridge with a new one.

The present invention therefore aims to provide a high concentration semaglutin formulation with optimized phenol concentration that is stable and capable of being delivered by a multi-dose reusable pen.

Disclosure of Invention

The present disclosure relates to a high concentration semaglutin liquid composition delivered by a reusable pen-type injector device. In one embodiment, a pen injector device includes one or more cartridges (cartridge) adapted to deliver multiple doses of semaglutin. The invention also relates to certain liquid pharmaceutical compositions comprising semaglutin at a concentration of 3mg/mL to 25mg/mL and phenol at a concentration of 0.11% w/w to 0.5% w/w.

Mode for carrying out the invention

In one embodiment, the present invention provides a liquid pharmaceutical composition comprising semaglutin and phenol at a concentration of 0.11% w/w to 0.5% w/w, and one or more pharmaceutically acceptable excipients.

In another embodiment, the invention provides a liquid pharmaceutical composition comprising high concentration of semaglutin and phenol at a concentration of 0.11% w/w to 0.5% w/w, and one or more pharmaceutically acceptable excipients.

In another embodiment, the invention provides a liquid pharmaceutical composition comprising semaglutin at a concentration of 3mg/mL to 25mg/mL and phenol at a concentration of 0.11% w/w to 0.5% w/w, and one or more pharmaceutically acceptable excipients.

In another embodiment, the liquid pharmaceutical composition of the invention is suitable for the treatment of type 2 diabetes and for the treatment of obesity.

In another embodiment, the present invention provides a method for preparing a liquid pharmaceutical composition comprising semaglutin and phenol at a concentration of 0.11% w/w to 0.5% w/w, and one or more pharmaceutically acceptable excipients.

In one embodiment, the present invention provides a liquid pharmaceutical composition comprising semaglutin and phenol at a concentration of 0.11% w/w to 0.5% w/w, and one or more pharmaceutically acceptable excipients, the composition being delivered using a reusable multi-dose drug delivery device.

In one embodiment, the present invention provides a liquid pharmaceutical composition comprising semaglutin and phenol at a concentration of 0.11% w/w to 0.5% w/w, and one or more pharmaceutically acceptable excipients, the composition being delivered using a reusable pen injector device, wherein the pen injector has a cartridge suitable for delivering a plurality of variable doses of semaglutin.

In another embodiment, the invention provides a cartridge comprising a liquid pharmaceutical composition of semaglutin, wherein the concentration of semaglutin is 3mg/mL to 25mg/mL, and the concentration of phenol is 0.11% w/w to 0.5% w/w.

In one embodiment, the invention provides a liquid pharmaceutical composition comprising semaglutin delivered using a reusable pen injector device, wherein the concentration of phenol in the formulation is about 0.11% w/w to 0.5% w/w. In addition, pen injectors have cartridges suitable for delivering multiple variable doses of semaglutin.

Detailed Description

The term "therapeutically effective amount" or "therapeutic dose" as used anywhere in the specification refers to an amount of a compound/drug/composition for treating a disease but low enough to avoid any serious side effects/toxicity/irritation or allergic response.

The term "high concentration of semaglutin" refers to a formulation comprising about 3mg/ml to 25mg/ml semaglutin.

The term "treating" as used anywhere in the specification means preventing or reducing or delaying the progression of clinical symptoms of a disease or disorder.

The term "RLD" refers to a reference Drug (REFERENCE LISTED Drug).

The present invention relates to a liquid pharmaceutical composition comprising:

(a) Semaglutin;

(b) 0.11% w/w to 0.5% w/w phenol;

(c) A buffering agent;

(d) One or more pharmaceutically acceptable excipients;

(e) And (3) water.

The liquid pharmaceutical composition as disclosed above, wherein the concentration of semaglutin is about 3.0mg/mL to about 25.0mg/mL. In yet another embodiment, a pharmaceutical composition of semaglutin is disclosed, wherein the concentration of semaglutin is about 3.5mg/mL to 20.0mg/mL. In yet another embodiment, a pharmaceutical composition of semaglutin is disclosed, wherein the concentration of semaglutin is about 4mg/mL to 15.0mg/mL. In yet another embodiment, a pharmaceutical composition of semaglutin is disclosed, wherein the concentration of semaglutin is about 4.5mg/mL to 10.0mg/mL. In yet another embodiment, a pharmaceutical composition of semaglutin is disclosed, wherein the concentration of semaglutin is about 5mg/mL to 10.0mg/mL. In yet another embodiment, a pharmaceutical composition of semaglutin is disclosed, wherein the concentration of semaglutin is about 5.5mg/mL to 10.0mg/mL. It should be understood that the range of 3mg/mL to about 25.0mg/mL includes all intermediate concentration ranges that may be prepared by the skilled artisan. In a preferred embodiment, a pharmaceutical composition of semaglutin is disclosed, wherein the concentration of semaglutin is about 4.8mg/mL to 6.0mg/mL.

A liquid pharmaceutical composition of semaglutin as disclosed above wherein the concentration of phenol is about 0.11% w/w to 0.5% w/w. In yet another embodiment, a pharmaceutical composition of semaglutin is provided wherein the concentration of phenol is about 0.15% w/w to 0.4% w/w. In yet another embodiment, a pharmaceutical composition of semaglutin is provided wherein the concentration of phenol is about 0.2% w/w to 0.3% w/w. It should be understood that the range of 0.11% w/w to 0.5% w/w includes all intermediate concentration ranges that may be prepared by the skilled artisan. In a preferred embodiment, a pharmaceutical composition of semaglutin is provided wherein the concentration of phenol is about 0.25% w/w to 0.35% w/w.

A liquid pharmaceutical composition of semaglutin as disclosed above, comprising a buffer, such as phosphate buffer, TRIS, citrate, or no buffer. In some embodiments, phosphate buffers are preferred, and such phosphate buffers are sodium phosphate buffers, such as disodium hydrogen phosphate dihydrate.

The buffer is used at a concentration of about 0.5mg/mL to about 1.5mg/mL. In yet another embodiment, a pharmaceutical composition of semaglutin is provided, wherein the buffer has a concentration of about 0.5mg/mL to 1.0mg/mL. In yet another embodiment, a pharmaceutical composition of semaglutin is provided, wherein the buffer has a concentration of about 1mg/mL to 1.5mg/mL. In a preferred embodiment, the concentration of buffer in the pharmaceutical composition is about 1.4mg/mL to 1.5mg/mL.

One or more pharmaceutically acceptable excipients are isotonic agents. The isotonic agent is propylene glycol or sodium chloride.

In a preferred embodiment, the isotonic agent is propylene glycol.

The concentration of the isotonic agent is from about 1mg/mL to about 20mg/mL. In yet another embodiment, a pharmaceutical composition of semaglutin is provided, wherein the concentration of the isotonic agent is about 4mg/mL to 16mg/mL. In yet another embodiment, a pharmaceutical composition of semaglutin is provided, wherein the concentration of the isotonic agent is about 8mg/mL to 12mg/mL. In a preferred embodiment, the concentration of the isotonic agent in the pharmaceutical composition is from about 10mg/mL to 16mg/mL.

The pH of the compositions of the invention ranges from 3 to 10, such as pH 6 to 10 or pH 6 to 9 and all possible pH values in between. In some embodiments, the pH of the compositions of the present invention ranges from pH 6.5 to 8.5, more preferably from pH 7.0 to 7.8.

The volume of water to be added adjusts the total volume of the composition to 1mL or the desired volume.

The compositions of the present invention are useful for parenteral administration. In some embodiments, the composition is for subcutaneous administration.

In another embodiment, a pharmaceutical composition of a semaglutin liquid of the invention is filled into a multi-dose container.

In some embodiments, the liquid pharmaceutical compositions of semaglutin of the present invention are useful for treating type 2 diabetes and for treating obesity.

In another embodiment, a process for preparing a liquid pharmaceutical composition of semaglutin of the present invention is provided, as follows:

1. First, water for injection (WFI) is collected at 80% of the target batch size (target batch size) and dissolved oxygen in the WFI is controlled to less than 2ppm;

2. Adding a proper buffer into the WFI in the step 1 and stirring until dissolved;

3. adding phenol into the solution in the step 1 and stirring until the phenol is dissolved;

4. adding a proper isotonic agent into the solution in the step 1 and stirring until the isotonic agent is dissolved;

5. Adding the semaglutin into the solution in the step 1 and stirring until the semaglutin is dissolved;

6. the pH of the above solution was adjusted to pH 7.4 using 0.5% w/v sodium hydroxide and/or 0.5% w/v hydrochloric acid;

7. make up the volume to the target lot size using WFI;

8. the drug solution (bulk) was filtered through a 0.22 μ filter and filled into a 3mL cartridge.

Surprisingly, it has been found that phenol at a concentration of about 0.11% w/w to 0.5% w/w helps to stabilize the liquid pharmaceutical composition of the present invention.

In a preferred embodiment, the stable liquid pharmaceutical composition of the present invention comprises 4.8mg/mL of semaglutin, 0.35% w/w phenol, 1.42mg of disodium hydrogen phosphate dihydrate, 14mg/mL propylene glycol, and water.

The present invention relates to a high concentration semaglutin liquid composition delivered by a reusable pen-type injector device.

In one embodiment, the invention includes a liquid pharmaceutical composition of semaglutin, wherein the concentration of semaglutin is about 3.0mg/mL to about 25.0mg/mL. In yet another embodiment, a pharmaceutical composition of semaglutin is disclosed, wherein the concentration of semaglutin is about 3.5mg/mL to 20.0mg/mL. In yet another embodiment, a pharmaceutical composition of semaglutin is disclosed, wherein the concentration of semaglutin is about 4mg/mL to 15.0mg/mL. In yet another embodiment, a pharmaceutical composition of semaglutin is disclosed, wherein the concentration of semaglutin is about 4.5mg/mL to 10.0mg/mL. In yet another embodiment, a pharmaceutical composition of semaglutin is disclosed, wherein the concentration of semaglutin is about 5mg/mL to 10.0mg/mL. In yet another embodiment, a pharmaceutical composition of semaglutin is disclosed, wherein the concentration of semaglutin is about 5.5mg/mL to 10.0mg/mL. It should be understood that the range of 3mg/mL to about 25.0mg/mL includes all intermediate concentration ranges that may be prepared by the skilled artisan. In a preferred embodiment, a pharmaceutical composition of semaglutin is disclosed, wherein the concentration of semaglutin is about 4.8mg/mL to 6.0mg/mL.

Furthermore, a high concentration semaglutin liquid composition wherein the concentration of phenol is about 0.11% w/w to 0.5% w/w. In yet another embodiment, a pharmaceutical composition of semaglutin is provided wherein the concentration of phenol is about 0.15% w/w to 0.4% w/w. In yet another embodiment, a pharmaceutical composition of semaglutin is provided wherein the concentration of phenol is about 0.2% w/w to 0.3% w/w. It should be understood that the range of 0.11% w/w to 0.5% w/w includes all intermediate concentration ranges that may be prepared by the skilled artisan. In a preferred embodiment, a pharmaceutical composition of semaglutin is provided wherein the concentration of phenol is about 0.25% w/w to 0.35% w/w.

The high concentration semaglutin liquid composition further comprises a buffer, such as phosphate buffer, TRIS, citrate, or is free of buffer. In some embodiments, phosphate buffers are preferred, and such phosphate buffers are sodium phosphate buffers, such as disodium hydrogen phosphate dihydrate.

A high concentration semaglutin liquid composition wherein the buffer concentration is from about 0.5mg/mL to about 1.5mg/mL. In yet another embodiment, a pharmaceutical composition of semaglutin is provided, wherein the buffer has a concentration of about 0.5mg/mL to 1.0mg/mL. In yet another embodiment, a pharmaceutical composition of semaglutin is provided, wherein the buffer has a concentration of about 1mg/mL to 1.5mg/mL.

In a preferred embodiment, the concentration of buffer in the pharmaceutical composition is about 1.4mg/mL to 1.5mg/mL.

The high concentration semaglutin liquid composition further comprises one or more pharmaceutically acceptable excipients.

The high concentration semaglutin liquid composition comprises an isotonic agent. In some embodiments, the isotonic agent is propylene glycol or sodium chloride.

In a preferred embodiment, the isotonic agent is propylene glycol.

A high concentration semaglutin liquid composition wherein the concentration of isotonic agent is from about 1mg/mL to about 20mg/mL. In yet another embodiment, a pharmaceutical composition of semaglutin is provided, wherein the concentration of the isotonic agent is about 4mg/mL to 16mg/mL. In yet another embodiment, a pharmaceutical composition of semaglutin is provided, wherein the concentration of the isotonic agent is about 8mg/mL to 12mg/mL. In a preferred embodiment, the concentration of the isotonic agent in the pharmaceutical composition is from about 10mg/mL to 16mg/mL.

The high concentration semaglutin liquid composition comprises water, wherein the volume of water to be added adjusts the total volume of the composition to 1mL or the desired volume.

The high concentration semaglutin liquid composition has a pH in the range of 3-10, such as pH 6-10 or pH 6-9 and all possible pH values in between. In some embodiments, the pH of the compositions of the present invention ranges from pH 6.5 to 8.5, more preferably from pH7.0 to 7.8.

In another embodiment, the high concentration semaglutin liquid composition of the present invention is filled into a multi-dose container.

In some embodiments, the high concentration semaglutin liquid compositions of the present invention are useful for treating type 2 diabetes and for treating obesity.

Surprisingly, it was found that high concentrations of semaglutin can be stabilized when phenol is used at a concentration of about 0.11% w/w to 0.5% w/w.

In one embodiment, the present invention provides a multi-dose delivery device for delivering a liquid pharmaceutical composition of semaglutin, wherein the concentration of phenol is 0.11% w/w to 0.5% w/w.

A multi-dose delivery device for delivering a liquid pharmaceutical composition of semaglutin, wherein the concentration of semaglutin is 3.0mg/ml to 25.0mg/ml.

In one embodiment, the present invention provides a liquid pharmaceutical composition of semaglutin delivered using a reusable multi-dose drug delivery device, wherein the concentration of semaglutin is 3.0mg/mL to 25.0mg/mL, and the concentration of phenol is 0.11% w/w to 0.5% w/w.

In one embodiment, the present invention provides a liquid pharmaceutical composition of semaglutin delivered using a reusable pen injector device, wherein the pen injector has a cartridge adapted for delivering a plurality of variable doses of the semaglutin liquid pharmaceutical composition.

In some embodiments, the present invention provides a liquid pharmaceutical composition of semaglutin disposed in a multi-dose drug delivery device adapted for administering a 0.25mg dose of semaglutin to 2.4mg semaglutin to a patient via a single device for treating type 2 diabetes and obesity.

In some embodiments, the present invention provides a liquid pharmaceutical composition of semaglutin in a multi-dose drug delivery device adapted for administering a dose of semaglutin to 2mg semaglutin to a patient via a single device for treating type 2 diabetes.

In some embodiments, the present invention provides a liquid pharmaceutical composition of semaglutin disposed in a multi-dose drug delivery device adapted for administering a 0.25mg dose of semaglutin to 2.4mg semaglutin to a patient via a single device for treating obesity.

In one embodiment, the multi-dose drug delivery device is a reusable pen injector.

In another embodiment, the invention provides a cartridge comprising a liquid pharmaceutical composition of semaglutin, wherein the semaglutin is at a concentration of 3mg/ml to 25mg/ml and the phenol is at a concentration of 0.11% w/w to 0.5% w/w, further comprising a buffer, a pharmaceutically acceptable excipient as disclosed throughout the specification, and water.

The liquid pharmaceutical composition of semaglutin according to the present invention is provided in a plurality of cartridges with reusable pen injectors.

The device comprises:

Reusable pen-type injector:

a plurality of cartridges are provided with reusable pen injectors. Once the desired number of doses from a single cartridge are delivered, the cartridge can be removed from the reusable device and a new filled cartridge can be loaded into the device to deliver the doses according to the therapeutic requirements. The user's steps mainly involve priming (pen) the pen, setting (dialing) the target dose and injecting the dose at the target injection site.

In one embodiment, the present invention provides a high concentration semaglutin liquid composition for delivery using a reusable pen injector device, wherein the pen injector comprises a cartridge adapted to deliver multiple doses of semaglutin according to patient treatment requirements.

In addition, semaglutin is sensitive to sunlight and degrades when exposed directly to sunlight. Thus, to protect the semaglutin from direct sunlight, the cartridge is made of a suitable material or packaged in a blister pack (blister pack).

In addition to the reusable feature, the proposed pen injector is also capable of delivering variable doses. This would enable the delivery of multiple doses according to the dose schedule required for weight management and type 2 diabetes treatment. Details of a representative number of doses that can be delivered, for example, loaded at one time in a 3mL filled cartridge, are shown in the following table.

TABLE 1 number of doses per device at different concentration of semaglutin per device

TABLE 2 RLD device vs device used in the present invention-for type 2 diabetes

TABLE 3 RLD device vs device for use in the present invention-for weight management

One advantage of a pen injector is that it provides a mechanism by which multiple doses of medication can be reliably delivered by a single pen injector. The same device can deliver different doses in approved dosage forms (which can be delivered by different devices) for type 2 diabetes treatment as well as weight management.

Another advantage is that the pen injector is provided with a mechanism that will never deliver a volume of medication greater than the selected volume of the patient. Yet another advantage is that the pen cap can be provided with a cartridge that can be replaced and the pen injector can be reused for drug delivery, the patient does not have to purchase a new pen injector every time a refill is needed, which also makes the invention cost-effective.

Table 4 compositions of semaglutin in multi-dose reusable pen injectors according to the present invention. (weight management)

The currently approved product is a single dose disposable auto-injector (each device can deliver only one dose)

TABLE 5 semaglutin composition (type 2 diabetes) in a multi-dose reusable pen injector according to the present invention

The currently approved product is a multi-dose disposable pen injector, but with different doses using different devices (device 1:0.25mg, 0.5mg; device 2:1mg; device 3:2 mg)

The present invention thus relates to a multi-dose reusable pen injector that delivers different doses from a single device and is suitable for both effective treatment of type 2 diabetes and weight management treatment. Each device can deliver different doses according to the dosage regimen necessary to effectively develop type 2 diabetes treatment and weight management. From a single cartridge/device, an effective dose of 0.25mg of semaglutin to 2.4mg of semaglutin can be provided to the patient by a single device. Thus, multiple doses, such as 0.25mg/0.5mg/1mg/1.7mg/2mg/2.4mg, can be provided to a patient in need thereof. This will significantly reduce costs for the patient. The pen injector device may also be reused by replacing a new cartridge multiple times to deliver the required number of doses.

The invention has the advantages compared with the prior therapy that:

high concentration, stable semaglutin formulation.

Variable different doses of multiple doses may be delivered from a single device.

The device can be reused by replacing a new cartridge.

Is a cost-effective option for the patient.

Better patient compliance with adherence to long-term treatment.

The following are non-limiting examples of high concentration, stable semaglutin formulations. These embodiments are illustrative and represent the preferred modes of carrying out the invention. The scope of the invention is not limited to the specific embodiments, but should be construed in view of the information and knowledge disclosed elsewhere in the specification and the general understanding of the scope of those skilled in the art.

Examples

Example 1:

Sequence number	Composition of the components	Dosage of
			1	Semiglutide	4.8mg/mL
2	Disodium hydrogen phosphate dihydrate	1.42mg/mL
			3	Propylene glycol	14mg/mL
4	Phenol (P)	1.5mg/mL
			5	Sodium hydroxide	Q.s. to pH7.4
6	Hydrochloric acid	Q.s. to pH7.4
			7	Water for injection	Q.s. to batch size

Q.s. proper amount (sufficient amount)

Manufacturing procedure:

1. First, water for injection (WFI) was collected at 80% of the target batch size, and dissolved oxygen in the WFI was controlled to less than 2ppm.

2. Disodium hydrogen phosphate dihydrate was added to the WFI of step 1 and stirred until dissolved.

3. Phenol was added to the solution of step 1 and stirred until dissolved.

4. Propylene glycol was added to the solution of step1 and stirred until dissolved.

5. The semaglutin is added to the solution of step 1 and stirred until dissolved.

6. The pH of the above solution was adjusted to pH 7.4 using 0.5% w/v sodium hydroxide and/or 0.5% w/v hydrochloric acid.

7. Finally, the WFI is used to make up the volume to the target batch size, and if necessary, the dissolved oxygen in the WFI is controlled to less than 2ppm.

Stability studies have been performed on the composition of example 1 on the same day as well as after 1 week. The composition of example 1 was stored in glass vials (GLASS VIALS) and stability studies were performed at 2-8 ℃, 25 ℃ and 60% relative humidity, 40 ℃ and 75% relative humidity, respectively.

Stability study of example 1

Example 2:

Sequence number	Composition of the components	Dosage of
			1	Semiglutide	4.8mg/mL
2	Disodium hydrogen phosphate dihydrate	1.42mg/mL
			3	Propylene glycol	14mg/mL
4	Phenol (P)	3.5mg/mL
			5	Sodium hydroxide	Q.s. to pH7.4
6	Hydrochloric acid	Q.s. to pH7.4
			7	Water for injection	Q.s. to batch size

Q.s. proper manufacturing process:

3. Phenol was added to the solution of step 1 and stirred until dissolved.

8. The drug solution was filtered through a 0.22 μ filter and filled into a 3mL cartridge.

Stability studies have been performed on the composition of example 2 on the same day as well as after 1 week. The composition of example 2 was placed in a glass bottle and stability studies were performed at 2-8 ℃, 25 ℃ and 60% relative humidity, 40 ℃ and 75% relative humidity, respectively.

Stability study of example 2

Example 3:

Sequence number	Composition of the components	Dosage of
			1	Semiglutide	4.8mg/mL
2	Disodium hydrogen phosphate dihydrate	1.42mg/mL
			3	Propylene glycol	14mg/mL
4	Phenol (P)	5mg/mL
			5	Sodium hydroxide	Q.s. to pH7.4
6	Hydrochloric acid	Q.s. to pH7.4
			7	Water for injection	Q.s. to batch size

Q.s. proper amount

The manufacturing process comprises the following steps:

3. Phenol was added to the solution of step 1 and stirred until dissolved.

Stability studies have been performed on the composition of example 3 on the same day as well as after 1 week. The composition of example 3 was placed in a glass bottle and stability studies were performed at 2-8 ℃, 25 ℃ and 60% relative humidity, 40 ℃ and 75% relative humidity, respectively.

Example 3 stability study

Claims

1. A liquid pharmaceutical composition comprising:

(a) Semaglutin;

(b) 0.11% w/w to 0.5% w/w phenol;

(c) A buffering agent;

(d) One or more pharmaceutically acceptable excipients;

(e) And (3) water.

2. The liquid pharmaceutical composition of claim 1, wherein the concentration of semaglutin is 3.0mg/ml to 25.0mg/ml.

3. The liquid pharmaceutical composition of claim 1, wherein the concentration of semaglutin is 3.5mg/ml to 20.0mg/ml.

4. The liquid pharmaceutical composition of claim 1, wherein the concentration of semaglutin is 4mg/ml to 15.0mg/ml.

5. The liquid pharmaceutical composition of claim 1, wherein the concentration of semaglutin is 4.5mg/ml to 10.0mg/ml.

6. The liquid pharmaceutical composition of claim 1, wherein the concentration of semaglutin is 5.0mg/ml to 10.0mg/ml.

7. The liquid pharmaceutical composition of claim 1, wherein the concentration of semaglutin is 5.5mg/ml to 10.0mg/ml.

8. The liquid pharmaceutical composition of claim 1, wherein the concentration of semaglutin is 4.8mg/ml to 6.0mg/ml.

9. The liquid pharmaceutical composition of claim 1, wherein the concentration of phenol is 0.15% w/w to 0.4% w/w.

10. The liquid pharmaceutical composition of claim 1, wherein the concentration of phenol is 0.2% w/w to 0.3% w/w.

11. The liquid pharmaceutical composition of claim 1, wherein the concentration of phenol is 0.25% w/w to 0.35% w/w.

12. The liquid pharmaceutical composition of claim 1, wherein the buffer is disodium hydrogen phosphate dihydrate.

13. The liquid pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable excipient is an isotonic agent selected from propylene glycol or sodium chloride.

14. The liquid pharmaceutical composition of claim 1, wherein the composition is filled in a multi-dose container.

15. The liquid pharmaceutical composition of claim 1, wherein the pharmaceutical composition is useful for treating diabetes and obesity.

16. A process for preparing the liquid pharmaceutical composition of claim 1 comprising semaglutin, 0.11% w/w to 0.5% w/w phenol and one or more pharmaceutical excipients, and wherein the process comprises the steps of:

1. collecting water for injection (WFI) at 80% of the target batch size, and controlling dissolved oxygen in the WFI to less than 2ppm;

4. adding an isotonic agent into the solution in the step1 and stirring until the isotonic agent is dissolved;

7. complementing the volume to a target batch size using the WFI;

17. A liquid pharmaceutical composition comprising 4.8mg/ml semaglutin, 0.35% w/w phenol, 1.42mg disodium hydrogen phosphate dihydrate, 14mg propylene glycol, and water.

18. A high concentration semaglutin liquid composition, the composition being delivered using a reusable pen injector device.

19. The high concentration semaglutin liquid composition of claim 18, wherein the concentration of semaglutin is 3.0mg/ml to 25.0mg/ml.

20. The high concentration semaglutin liquid composition of claim 18, wherein the concentration of semaglutin is 3.5mg/ml to 20.0mg/ml.

21. The high concentration semaglutin liquid composition of claim 18, wherein the concentration of semaglutin is 4mg/ml to 15.0mg/ml.

22. The high concentration semaglutin liquid composition of claim 18, wherein the concentration of semaglutin is 4.5mg/ml to 10.0mg/ml.

23. The high concentration semaglutin liquid composition of claim 18, wherein the concentration of semaglutin is 5.0mg/ml to 10.0mg/ml.

24. The high concentration semaglutin liquid composition of claim 18, wherein the concentration of semaglutin is 5.5mg/ml to 10.0mg/ml.

25. The high concentration semaglutin liquid composition of claim 18, wherein the concentration of semaglutin is 4.8mg/ml to 6.0mg/ml.

26. The high concentration semaglutin liquid composition of claim 18, wherein the concentration of phenol is 0.11% w/w to 0.5% w/w.

27. The high concentration semaglutin liquid composition of claim 18, wherein the concentration of phenol is 0.15% w/w to 0.4% w/w.

28. The high concentration semaglutin liquid composition of claim 18, wherein the concentration of phenol is 0.2% w/w to 0.3% w/w.

29. The high concentration semaglutin liquid composition of claim 18, wherein the concentration of phenol is 0.25% w/w to 0.35% w/w.

30. The high concentration semaglutin liquid composition of claim 18, wherein the buffer is disodium hydrogen phosphate dihydrate.

31. The high concentration semaglutin liquid composition of claim 18, wherein the pharmaceutically acceptable excipient is an isotonic agent selected from propylene glycol or sodium chloride.

32. The high concentration semaglutin liquid composition of claim 18, wherein the composition is filled in a multi-dose container.

33. The high concentration semaglutin liquid composition of claim 18, wherein the pharmaceutical composition is useful for treating diabetes and obesity.

34. A multi-dose delivery device for delivering a liquid pharmaceutical composition of semaglutin, wherein the concentration of phenol is 0.11% w/w to 0.5% w/w.

35. The multi-dose delivery device of claim 34 for delivering a liquid pharmaceutical composition of semaglutin, wherein the concentration of semaglutin is 3.0mg/ml to 25.0mg/ml.

36. The multi-dose delivery device of claim 34, the device being comprised of a cartridge of a liquid pharmaceutical composition suitable for delivering a plurality of variable doses of semaglutin.

37. The multi-dose delivery device of claim 34 for delivering a dose of semaglutin ranging from 0.25mg to 2mg for the treatment of diabetes.

38. The multi-dose delivery device of claim 34 for delivering a dose of semaglutin ranging from 0.25mg to 2.4mg for the treatment of obesity.

39. A multi-dose delivery device as claimed in claim 34, which is a reusable pen injector device.

40. A cartridge comprising a liquid pharmaceutical composition of semaglutin, wherein the semaglutin is at a concentration of 3mg/ml to 25mg/ml and the phenol is at a concentration of 0.11% w/w to 0.5% w/w, having a buffer, a pharmaceutically acceptable excipient and water.

41. The liquid pharmaceutical composition of semaglutin according to claim 40 provided in a plurality of cartridges having reusable pen injectors.