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

Abstract

It is an object of the present invention to provide a liquid composition of semeglutide having phenol at a concentration of from 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 semeglutide and a method for treating diabetes and obesity by using the composition.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition of semaglutide, which is delivered by a reusable pen injector device. In one embodiment, the pen injector device comprises one or more cartridges suitable for delivering multiple doses and different variable doses of semaglutide for the treatment of type 2 diabetes and weight management. The present invention also relates to a novel liquid pharmaceutical composition comprising semaglutide at a concentration of 3 mg / mL to 25 mg / mL and phenol at a concentration of 0.11% w / w to 0.5% w / w. Background Art

[0002] Semaglutide is one of the effective drugs for the treatment of type 2 diabetes and weight management. The drug has been approved for oral and injection forms.

[0003] WO2006097537 first disclosed semaglutide. The same document also disclosed certain injectable compositions of semaglutide.

[0004] Semaglutide is a long-acting human glucagon-like peptide-1 analog, Aib 8 , Arg 34 -GLP-1(7-37) analogue, which is substituted by a (S)-22,40-dicarboxy-10,19,24-trioxo-3,6,12,15-tetraoxa-9,18,23-triazatetracontan-1-yl side chain on the ε-lysine residue at position 26. The side chain consists of two 8-amino-3,6-dioxaoctanoic acid (ADO) spacers, a γ-glutamic acid (Glu) spacer and a fatty diacid (1,18-octadecandioic acid). Pharmaceutical dosage forms containing semaglutide have been disclosed in WO2006097537 and WO2019038412. There are currently two approved brands of semaglutide injection, namely and .

[0005] It is approved for the treatment of diabetes and is available in a disposable pen-type syringe and in different devices for different doses (Device 1: 0.25 mg, 0.5 mg; Device 2: 1 mg; Device 3: 2 mg). It is available as a solution for subcutaneous injection, in which the concentration of phenol is 5.5 mg / ml.

[0006] Supplied as a clear, colorless solution for subcutaneous injection in a 1 mL prefilled Type I glass syringe (PFS) 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) prefilled pen (PFP). It is available in packages of 4 PFPs, each containing: - 0.5 mL contains 0.25 mg semaglutide (content (specification, strength) 0.25 mg); - 0.5 mL contains 0.5 mg semaglutide (content 0.5 mg); - 0.5 mL contains 1 mg semaglutide (content 1 mg); - 0.75 mL contains 1.7 mg semaglutide (content 1.7 mg); - 0.75 mL contains 2.4 mg semaglutide (content 2.4 mg).

[0007] Approved injections One of the major disadvantages of semaglutide formulations is that the injectable dosage form is available either as a single disposable pen-injector or as a fixed-dose, multi-dose syringe. Therefore, patients need to use / purchase a disposable pen every week or purchase different pen-injectors for different doses throughout the treatment cycle according to the approved dosage regimen. The pen provided for injection is a single-use pen that should be discarded after each dose. This not only increases the cost of treatment for patients, but also generates unnecessary waste and has an impact on the environment.

[0008] In addition, as explained in WO2019038412, when a higher amount of phenol is used to formulate a higher dose of semaglutide required for weight management treatment, the semaglutide liquid formulation is unstable. Therefore, the WO'412 document discloses a semaglutide formulation that does not contain phenol or contains a negligible amount of phenol. This typical semaglutide formulation is likely to have to use a disposable pen when used for drug delivery.

[0009] Therefore, there is a need to research and develop a new semaglutide formulation that is more cost-effective for patients, stable enough to avoid the use of disposable pens (single-use pens) for delivery, provides better patient compliance, and is environmentally friendly. The inventors of the present invention surprisingly found that by optimizing the concentration of phenol in the formulation, it is possible to formulate a higher concentration of semaglutide without affecting its stability. With such a stable formulation, multiple doses of semaglutide can be delivered using a multi-dose syringe device containing a cartridge, and the device can be reused by replacing a new cartridge.

[0010] Therefore, the present invention aims to provide a high concentration semaglutide formulation with an optimized phenol concentration, which is stable and can be delivered via a multi-dose reusable pen. Summary of the invention

[0011] The present disclosure relates to a high concentration semaglutide liquid composition, which is delivered by a reusable pen injector device. In one embodiment, the pen injector device includes one or more cartridges suitable for delivering multiple doses of semaglutide. The present invention also relates to certain liquid pharmaceutical compositions, which contain semaglutide at a concentration of 3 mg / mL to 25 mg / mL and phenol at a concentration of 0.11% w / w to 0.5% w / w.

[0012] Mode for carrying out the invention

[0013] In one embodiment, the present invention provides a liquid pharmaceutical composition comprising semaglutide and phenol at a concentration of 0.11% w / w to 0.5% w / w, and one or more pharmaceutically acceptable excipients.

[0014] In another embodiment, the present invention provides a liquid pharmaceutical composition comprising high concentration semaglutide and phenol at a concentration of 0.11% w / w to 0.5% w / w, and one or more pharmaceutically acceptable excipients.

[0015] In another embodiment, the present invention provides a liquid pharmaceutical composition comprising semaglutide at a concentration of 3 mg / mL to 25 mg / mL and phenol at a concentration of 0.11% w / w to 0.5% w / w, and one or more pharmaceutically acceptable excipients.

[0016] In another embodiment, the liquid pharmaceutical composition of the present invention is suitable for treating type 2 diabetes and treating obesity.

[0017] In another embodiment, the present invention provides a method for preparing a liquid pharmaceutical composition comprising semaglutide and phenol at a concentration of 0.11% w / w to 0.5% w / w, and one or more pharmaceutically acceptable excipients.

[0018] In one embodiment, the present invention provides a liquid pharmaceutical composition comprising semaglutide and phenol at a concentration of 0.11% w / w to 0.5% w / w, and one or more pharmaceutically acceptable excipients, which is delivered using a reusable multi-dose drug delivery device.

[0019] In one embodiment, the present invention provides a liquid pharmaceutical composition comprising semaglutide and phenol at a concentration of 0.11% w / w to 0.5% w / w, and one or more pharmaceutically acceptable excipients, which composition is delivered using a reusable pen injector device, wherein the pen injector has a cartridge suitable for delivering multiple variable doses of semaglutide.

[0020] In another embodiment, the present invention provides a cartridge comprising a liquid pharmaceutical composition of semaglutide, wherein the concentration of semaglutide is 3 mg / mL to 25 mg / mL, and the concentration of phenol is 0.11% w / w to 0.5% w / w.

[0021] In one embodiment, the present invention provides a liquid pharmaceutical composition comprising semaglutide, which is 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, the pen injector has a cartridge suitable for delivering multiple variable doses of semaglutide. DETAILED DESCRIPTION

[0022] The term "therapeutically effective amount" or "therapeutic dose" used anywhere in the specification refers to an amount of a compound / drug / composition that is useful for treating a disease but is low enough to avoid any serious side effects / toxicity / irritation or allergic reactions.

[0023] The term "high concentration semaglutide" refers to a formulation comprising about 3 mg / ml to 25 mg / ml of semaglutide.

[0024] The term "treat" as used anywhere in the specification refers to preventing or reducing or delaying the progression of clinical symptoms of a disease or disorder.

[0025] The term "RLD" refers to Reference Listed Drug.

[0026] The present invention relates to a liquid pharmaceutical composition comprising:

[0027] (a) semaglutide;

[0028] (b) 0.11% w / w to 0.5% w / w phenol;

[0029] (c) buffers;

[0030] (d) one or more pharmaceutically acceptable excipients;

[0031] (e) Water.

[0032] A liquid pharmaceutical composition as disclosed above, wherein the concentration of semaglutide is about 3.0 mg / mL to about 25.0 mg / mL. In another embodiment, a pharmaceutical composition of semaglutide is disclosed, wherein the concentration of semaglutide is about 3.5 mg / mL to 20.0 mg / mL. In another embodiment, a pharmaceutical composition of semaglutide is disclosed, wherein the concentration of semaglutide is about 4 mg / mL to 15.0 mg / mL. In another embodiment, a pharmaceutical composition of semaglutide is disclosed, wherein the concentration of semaglutide is about 4.5 mg / mL to 10.0 mg / mL. In another embodiment, a pharmaceutical composition of semaglutide is disclosed, wherein the concentration of semaglutide is about 5 mg / mL to 10.0 mg / mL. In another embodiment, a pharmaceutical composition of semaglutide is disclosed, wherein the concentration of semaglutide is about 5.5 mg / mL to 10.0 mg / mL. It should be understood that the range of 3 mg / mL to about 25.0 mg / mL includes all intermediate concentration ranges that may be prepared by a skilled artisan. In a preferred embodiment, a pharmaceutical composition of semaglutide is disclosed, wherein the concentration of semaglutide is about 4.8 mg / mL to 6.0 mg / mL.

[0033] A liquid pharmaceutical composition of semaglutide as disclosed above, wherein the concentration of phenol is about 0.11% w / w to 0.5% w / w. In another embodiment, a pharmaceutical composition of semaglutide is provided, wherein the concentration of phenol is about 0.15% w / w to 0.4% w / w. In another embodiment, a pharmaceutical composition of semaglutide 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 a skilled person. In a preferred embodiment, a pharmaceutical composition of semaglutide is provided, wherein the concentration of phenol is about 0.25% w / w to 0.35% w / w.

[0034] The liquid pharmaceutical composition of semaglutide disclosed above, wherein a buffer is included, such as phosphate buffer, TRIS, citrate, or no buffer. In some embodiments, a phosphate buffer is preferred, and such a phosphate buffer is a sodium phosphate buffer, such as disodium hydrogen phosphate dihydrate.

[0035] The concentration of the buffer used is about 0.5 mg / mL to about 1.5 mg / mL. In another embodiment, a pharmaceutical composition of semaglutide is provided, wherein the concentration of the buffer is about 0.5 mg / mL to 1.0 mg / mL. In another embodiment, a pharmaceutical composition of semaglutide is provided, wherein the concentration of the buffer is about 1 mg / mL to 1.5 mg / mL. In a preferred embodiment, the concentration of the buffer in the pharmaceutical composition is about 1.4 mg / mL to 1.5 mg / mL.

[0036] One or more pharmaceutically acceptable excipients are isotonic agents. The isotonic agent is propylene glycol or sodium chloride.

[0037] In a preferred embodiment, the isotonicity agent is propylene glycol.

[0038] The concentration of the isotonic agent is about 1 mg / mL to about 20 mg / mL. In another embodiment, a pharmaceutical composition of semaglutide is provided, wherein the concentration of the isotonic agent is about 4 mg / mL to 16 mg / mL. In another embodiment, a pharmaceutical composition of semaglutide is provided, wherein the concentration of the isotonic agent is about 8 mg / mL to 12 mg / mL. In a preferred embodiment, the concentration of the isotonic agent in the pharmaceutical composition is about 10 mg / mL to 16 mg / mL.

[0039] The pH value of the composition of the present invention ranges from 3 to 10, such as pH 6 to 10 or pH 6 to 9 and all possible pH values ​​therebetween. In some embodiments, the pH value of the composition of the present invention ranges from pH 6.5 to 8.5, more preferably pH 7.0 to 7.8.

[0040] The volume of water to be added is such that the total volume of the composition is adjusted to 1 mL or the desired volume.

[0041] The compositions of the present invention are for parenteral administration. In some embodiments, the compositions are for subcutaneous administration.

[0042] In another embodiment, the semaglutide liquid pharmaceutical composition of the present invention is filled into a multi-dose container.

[0043] In some embodiments, the liquid pharmaceutical composition of semaglutide of the present invention is suitable for treating type 2 diabetes and treating obesity.

[0044] In another embodiment, a method for preparing a liquid pharmaceutical composition of semaglutide of the present invention is provided, as described below:

[0045] 1. First, collect water for injection (WFI) at 80% of the target batch size and control the dissolved oxygen in WFI to less than 2 ppm;

[0046] 2. Add a suitable buffer to the WFI in step 1 and stir until dissolved;

[0047] 3. Add phenol to the solution in step 1 and stir until dissolved;

[0048] 4. Add a suitable isotonic agent to the solution in step 1 and stir until dissolved;

[0049] 5. Add semaglutide to the solution in step 1 and stir until dissolved;

[0050] 6. Use 0.5% w / v sodium hydroxide and / or 0.5% w / v hydrochloric acid to adjust the pH value of the above solution to pH 7.4;

[0051] 7. Use WFI to make up the volume to the target batch size;

[0052] 8. Filter the bulk through a 0.22μ filter and fill in 3 mL cartridges.

[0053] The compositions of the present invention are for parenteral administration. In some embodiments, the compositions are for subcutaneous administration.

[0054] Surprisingly, it was found that phenol, when used 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.

[0055] In a preferred embodiment, the stable liquid pharmaceutical composition of the present invention comprises 4.8 mg / mL semaglutide, 0.35% w / w phenol, 1.42 mg disodium hydrogen phosphate dihydrate, 14 mg / mL propylene glycol and water.

[0056] The present invention relates to a high concentration semaglutide liquid composition which is delivered via a reusable pen injector device.

[0057] In one embodiment, the present invention includes a liquid pharmaceutical composition of semaglutide, wherein the concentration of semaglutide is about 3.0 mg / mL to about 25.0 mg / mL. In another embodiment, a pharmaceutical composition of semaglutide is disclosed, wherein the concentration of semaglutide is about 3.5 mg / mL to 20.0 mg / mL. In another embodiment, a pharmaceutical composition of semaglutide is disclosed, wherein the concentration of semaglutide is about 4 mg / mL to 15.0 mg / mL. In another embodiment, a pharmaceutical composition of semaglutide is disclosed, wherein the concentration of semaglutide is about 4.5 mg / mL to 10.0 mg / mL. In another embodiment, a pharmaceutical composition of semaglutide is disclosed, wherein the concentration of semaglutide is about 5 mg / mL to 10.0 mg / mL. In another embodiment, a pharmaceutical composition of semaglutide is disclosed, wherein the concentration of semaglutide is about 5.5 mg / mL to 10.0 mg / mL. It should be understood that the range of 3 mg / mL to about 25.0 mg / mL includes all intermediate concentration ranges that may be prepared by a skilled artisan. In a preferred embodiment, a pharmaceutical composition of semaglutide is disclosed, wherein the concentration of semaglutide is about 4.8 mg / mL to 6.0 mg / mL.

[0058] In addition, a high concentration semaglutide liquid composition, wherein the concentration of phenol is about 0.11% w / w to 0.5% w / w. In another embodiment, a pharmaceutical composition of semaglutide is provided, wherein the concentration of phenol is about 0.15% w / w to 0.4% w / w. In another embodiment, a pharmaceutical composition of semaglutide 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 technicians. In a preferred embodiment, a pharmaceutical composition of semaglutide is provided, wherein the concentration of phenol is about 0.25% w / w to 0.35% w / w.

[0059] The high concentration semaglutide liquid composition further comprises a buffer, such as phosphate buffer, TRIS, citrate, or contains no buffer. In some embodiments, a phosphate buffer is preferred, and such a phosphate buffer is a sodium phosphate buffer, such as disodium hydrogen phosphate dihydrate.

[0060] A high concentration semaglutide liquid composition, wherein the concentration of the buffer is about 0.5 mg / mL to about 1.5 mg / mL. In another embodiment, a pharmaceutical composition of semaglutide is provided, wherein the concentration of the buffer is about 0.5 mg / mL to 1.0 mg / mL. In another embodiment, a pharmaceutical composition of semaglutide is provided, wherein the concentration of the buffer is about 1 mg / mL to 1.5 mg / mL.

[0061] In a preferred embodiment, the concentration of the buffer in the pharmaceutical composition is about 1.4 mg / mL to 1.5 mg / mL.

[0062] The high-concentration semaglutide liquid composition further comprises one or more pharmaceutically acceptable excipients.

[0063] The high concentration semaglutide liquid composition comprises an isotonic agent. In some embodiments, the isotonic agent is propylene glycol or sodium chloride.

[0064] In a preferred embodiment, the isotonicity agent is propylene glycol.

[0065] A high concentration semaglutide liquid composition, wherein the concentration of the isotonic agent is about 1 mg / mL to about 20 mg / mL. In another embodiment, a pharmaceutical composition of semaglutide is provided, wherein the concentration of the isotonic agent is about 4 mg / mL to 16 mg / mL. In another embodiment, a pharmaceutical composition of semaglutide is provided, wherein the concentration of the isotonic agent is about 8 mg / mL to 12 mg / mL. In a preferred embodiment, the concentration of the isotonic agent in the pharmaceutical composition is about 10 mg / mL to 16 mg / mL.

[0066] The high-concentration semaglutide liquid composition comprises water, wherein the volume of water to be added is such that the total volume of the composition is adjusted to 1 mL or a desired volume.

[0067] The pH value of the high concentration semaglutide liquid composition ranges from 3 to 10, such as pH 6 to 10 or pH 6 to 9 and all possible pH values ​​therebetween. In some embodiments, the pH value of the composition of the present invention ranges from pH 6.5 to 8.5, more preferably pH 7.0 to 7.8.

[0068] The compositions of the present invention are for parenteral administration. In some embodiments, the compositions are for subcutaneous administration.

[0069] In another embodiment, the high-concentration semaglutide liquid composition of the present invention is filled in a multi-dose container.

[0070] In some embodiments, the high-concentration semaglutide liquid composition of the present invention is suitable for treating type 2 diabetes and treating obesity.

[0071] Surprisingly, it was found that high concentrations of semaglutide can be stabilized when phenol is used at a concentration of about 0.11% w / w to 0.5% w / w.

[0072] In one embodiment, the present invention provides a multi-dose delivery device for delivering a liquid pharmaceutical composition of semaglutide, wherein the concentration of phenol is 0.11% w / w to 0.5% w / w.

[0073] A multi-dose delivery device for delivering a liquid pharmaceutical composition of semaglutide, wherein the concentration of semaglutide is 3.0 mg / ml to 25.0 mg / ml.

[0074] In one embodiment, the present invention provides a liquid pharmaceutical composition of semaglutide delivered using a reusable multi-dose drug delivery device, wherein the concentration of semaglutide is 3.0 mg / mL to 25.0 mg / mL and the concentration of phenol is 0.11% w / w to 0.5% w / w.

[0075] In one embodiment, the present invention provides a liquid pharmaceutical composition of semaglutide that is delivered using a reusable pen injector device, wherein the pen injector has a cartridge suitable for delivering multiple variable doses of the liquid pharmaceutical composition of semaglutide.

[0076] In some embodiments, the present invention provides a liquid pharmaceutical composition of semaglutide placed in a multi-dose drug delivery device suitable for administering a dose of 0.25 mg semaglutide to 2.4 mg semaglutide to a patient via a single device for the treatment of type 2 diabetes and obesity.

[0077] In some embodiments, the present invention provides a liquid pharmaceutical composition of semaglutide placed in a multi-dose drug delivery device suitable for administering a dose of 0.25 mg semaglutide to 2 mg semaglutide to a patient via a single device for the treatment of type 2 diabetes.

[0078] In some embodiments, the present invention provides a liquid pharmaceutical composition of semaglutide placed in a multi-dose drug delivery device suitable for administering a dose of 0.25 mg semaglutide to 2.4 mg semaglutide to a patient via a single device to treat obesity.

[0079] In one embodiment, the multi-dose drug delivery device is a reusable pen injector.

[0080] In another embodiment, the present invention provides a cartridge comprising a liquid pharmaceutical composition of semaglutide, wherein the concentration of semaglutide is 3 mg / ml to 25 mg / ml, and the concentration of phenol is 0.11% w / w to 0.5% w / w, and further comprises a buffer, a pharmaceutically acceptable excipient as disclosed elsewhere in the specification, and water.

[0081] The liquid pharmaceutical composition of semaglutide according to the present invention is provided in a plurality of cartridges with a reusable pen injector.

[0082] Device:

[0083] Reusable pen injector:

[0084] Multiple cartridges are equipped with (provided with) a reusable pen injector. Once the required number of doses from a single cartridge has been delivered, the cartridge can be removed from the reusable device and a new filled cartridge can be loaded into the device to deliver doses according to the treatment requirements. The user's operating steps mainly involve priming the pen (pen injector), setting (dialing) the target dose, and injecting the dose at the target injection site.

[0085] In one embodiment, the present invention provides a high concentration semaglutide liquid composition that is delivered using a reusable pen injector device, wherein the pen injector comprises a cartridge suitable for delivering multiple doses of semaglutide according to the patient's treatment needs.

[0086] In addition, semaglutide is sensitive to sunlight and will degrade when directly exposed to sunlight. Therefore, to protect semaglutide from direct sunlight, the cartridge is made of suitable materials or packaged in a blister pack.

[0087] In addition to the reusable feature, the proposed pen injector is also capable of delivering variable doses. This will enable the delivery of multiple numbers of doses according to the dosage schedule required for weight management and type 2 diabetes treatment. For example, the details of the representative number of doses that can be delivered in one load in a 3 mL filling cartridge are shown in the following table.

[0088] Table 1: Number of doses per device at different semaglutide concentrations per device

[0089]

[0090] Table 2: RLD device vs. device used in the present invention - for type 2 diabetes

[0091]

[0092]

[0093] Table 3: RLD device vs. device used in the present invention - for weight management

[0094]

[0095] One advantage of a pen injector is that it provides a mechanism to reliably deliver multiple doses of medication through a single pen injector. The same device can deliver different doses in approved dosage forms that can be delivered by different devices for type 2 diabetes treatment as well as weight management.

[0096] Another advantage is that the pen injector is provided with a mechanism that will never deliver a volume of medication greater than the volume selected by the patient. Still 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 medication delivery without the patient having to purchase a new pen injector each time a refill is required, which also makes the invention cost effective.

[0097] Table 4: Composition of semaglutide in a multi-dose reusable pen injector according to the present invention. (Weight Management)

[0098] The currently approved product is a single-dose, disposable auto-injector (each device can only deliver one dose)

[0099]

[0100]

[0101]

[0102] Table 5: Composition of semaglutide in a multi-dose reusable pen injector according to the present invention (type 2 diabetes)

[0103] The currently approved product is a multi-dose disposable pen-injector, but different doses use different devices (Device 1: 0.25 mg, 0.5 mg; Device 2: 1 mg; Device 3: 2 mg)

[0104]

[0105] The present invention therefore 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 therapy. Each device can deliver different doses according to the dosage regimen necessary for effective type 2 diabetes treatment and weight management. From a single cartridge / device, an effective dose of 0.25 mg of semaglutide to 2.4 mg of semaglutide can be provided to a patient through a single device. Therefore, multiple doses such as 0.25 mg / 0.5 mg / 1 mg / 1.7 mg / 2 mg / 2.4 mg can be provided to patients in need. This will significantly reduce costs for patients. The pen injector device can also be reused multiple times by replacing a new cartridge to deliver the required number of doses.

[0106] The advantages of the present invention compared to existing therapies are:

[0107] ·High concentration and stable semaglutide preparation.

[0108] • Multiple doses of variable different doses can be delivered from a single device.

[0109] The device can be reused by replacing the new cartridge.

[0110] ·It is a cost-effective option for patients.

[0111] Better patient compliance through long-term treatment adherence.

[0112] The following are non-limiting examples of high-concentration, stable semaglutide formulations. These examples are illustrative and represent preferred modes of implementing the present invention. The scope of the present invention is not limited to these specific embodiments, but should be interpreted in conjunction with the contents disclosed elsewhere in the specification and the information and knowledge generally understood by those skilled in the art.

[0113] Example

[0114] Embodiment 1:

[0115] Serial number Element Dosage 1 Semaglutide 4.8 mg / mL 2 Disodium hydrogen phosphate dihydrate 1.42mg / mL 3 Propylene glycol 14 mg / mL 4 phenol 1.5mg / mL 5 Sodium hydroxide qs to pH 7.4 6 hydrochloric acid qs to pH 7.4 7 Water for injection qs to batch size

[0116] qs appropriate amount (sufficient amount)

[0117] Manufacturing process:

[0118] 1. First, collect water for injection (WFI) at 80% of the target batch size and control the dissolved oxygen in the WFI to less than 2 ppm.

[0119] 2. Add disodium hydrogen phosphate dihydrate to the WFI in step 1 and stir until dissolved.

[0120] 3. Add phenol to the solution in step 1 and stir until dissolved.

[0121] 4. Add propylene glycol to the solution in step 1 and stir until dissolved.

[0122] 5. Add semaglutide to the solution in step 1 and stir until dissolved.

[0123] 6. Adjust the pH of the above solution to pH 7.4 using 0.5% w / v sodium hydroxide and / or 0.5% w / v hydrochloric acid.

[0124] 7. Finally, make up the volume to the target batch size with WFI and, if necessary, control the dissolved oxygen in the WFI to less than 2 ppm.

[0125] 8. Filter the bulk through a 0.22μ filter and fill into 3 mL cartridges.

[0126] The stability study of the composition of Example 1 was conducted on the day of preparation and after 1 week. The composition of Example 1 was stored in glass vials and the stability study was conducted at 2-8°C, 25°C and 60% relative humidity, and 40°C and 75% relative humidity.

[0127] Stability Study of Example 1

[0128]

[0129]

[0130] Embodiment 2:

[0131] Serial number Element Dosage 1 Semaglutide 4.8 mg / mL 2 Disodium hydrogen phosphate dihydrate 1.42mg / mL 3 Propylene glycol 14 mg / mL 4 phenol 3.5mg / mL 5 Sodium hydroxide qs to pH 7.4 6 hydrochloric acid qs to pH 7.4 7 Water for injection qs to batch size

[0132] QS appropriate manufacturing process:

[0133] 1. First, collect water for injection (WFI) at 80% of the target batch size and control the dissolved oxygen in the WFI to less than 2 ppm.

[0134] 2. Add disodium hydrogen phosphate dihydrate to the WFI in step 1 and stir until dissolved.

[0135] 3. Add phenol to the solution in step 1 and stir until dissolved.

[0136] 4. Add propylene glycol to the solution in step 1 and stir until dissolved.

[0137] 5. Add semaglutide to the solution in step 1 and stir until dissolved.

[0138] 6. Adjust the pH of the above solution to pH 7.4 using 0.5% w / v sodium hydroxide and / or 0.5% w / v hydrochloric acid.

[0139] 7. Finally, make up the volume to the target batch size with WFI and, if necessary, control the dissolved oxygen in the WFI to less than 2 ppm.

[0140] 8. Filter the drug solution through a 0.22μ filter and fill into a 3mL cartridge.

[0141] The stability study of the composition of Example 2 was conducted on the day of preparation and after 1 week. The composition of Example 2 was placed in glass bottles and the stability study was conducted at 2-8°C, 25°C and 60% relative humidity, and 40°C and 75% relative humidity.

[0142] Stability Study of Example 2

[0143]

[0144]

[0145] Embodiment 3:

[0146] Serial number Element Dosage 1 Semaglutide 4.8 mg / mL 2 Disodium hydrogen phosphate dihydrate 1.42mg / mL 3 Propylene glycol 14 mg / mL 4 phenol 5mg / mL 5 Sodium hydroxide qs to pH 7.4 6 hydrochloric acid qs to pH 7.4 7 Water for injection qs to batch size

[0147] Qs appropriate amount

[0148] Manufacturing process:

[0149] 1. First, collect water for injection (WFI) at 80% of the target batch size and control the dissolved oxygen in the WFI to less than 2 ppm.

[0150] 2. Add disodium hydrogen phosphate dihydrate to the WFI in step 1 and stir until dissolved.

[0151] 3. Add phenol to the solution in step 1 and stir until dissolved.

[0152] 4. Add propylene glycol to the solution in step 1 and stir until dissolved.

[0153] 5. Add semaglutide to the solution in step 1 and stir until dissolved.

[0154] 6. Adjust the pH of the above solution to pH 7.4 using 0.5% w / v sodium hydroxide and / or 0.5% w / v hydrochloric acid.

[0155] 7. Finally, make up the volume to the target batch size with WFI and, if necessary, control the dissolved oxygen in the WFI to less than 2 ppm.

[0156] 8. Filter the drug solution through a 0.22μ filter and fill into a 3mL cartridge.

[0157] The stability study of the composition of Example 3 was conducted on the day of preparation and after 1 week. The composition of Example 3 was placed in glass bottles and the stability study was conducted at 2-8°C, 25°C and 60% relative humidity, and 40°C and 75% relative humidity.

[0158] Stability Study of Example 3

[0159]

[0160]

Claims

1. A liquid pharmaceutical composition comprising: (a) semaglutide; (b) 0.11% w / w to 0.5% w / w phenol; (c) buffers; (d) one or more pharmaceutically acceptable excipients; (e) Water.

2. The liquid pharmaceutical composition according to claim 1, wherein The concentration of semaglutide ranged from 3.0 mg / ml to 25.0 mg / ml.

3. The liquid pharmaceutical composition according to claim 1, wherein The concentration of semaglutide ranged from 3.5 mg / ml to 20.0 mg / ml.

4. The liquid pharmaceutical composition according to claim 1, wherein The concentration of semaglutide ranged from 4 mg / ml to 15.0 mg / ml.

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

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

7. The liquid pharmaceutical composition according to claim 1, wherein The concentration of semaglutide was 5.5 mg / ml to 10.0 mg / ml.

8. The liquid pharmaceutical composition according to claim 1, wherein The concentration of semaglutide was 4.8 mg / ml to 6.0 mg / ml.

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

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

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

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

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

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

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

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

1. Collect water for injection (WFI) at 80% of the target batch size and control the dissolved oxygen in WFI to less than 2 ppm; 2. Add a suitable buffer to the WFI in step 1 and stir until dissolved; 3. Add phenol to the solution in step 1 and stir until dissolved; 4. Add the isotonic agent to the solution in step 1 and stir until dissolved; 5. Add semaglutide to the solution in step 1 and stir until dissolved; 6. Adjust the pH of the above solution 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 batch size using the WFI; 8. Filter the drug solution through a 0.22μ filter and fill in a 3mL cartridge.

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

18. A high concentration semaglutide liquid composition delivered using a reusable pen injector device.

19. The high-concentration semaglutide liquid composition according to claim 18, wherein: The concentration of semaglutide ranged from 3.0 mg / ml to 25.0 mg / ml.

20. The high-concentration semaglutide liquid composition according to claim 18, wherein: The concentration of semaglutide ranged from 3.5 mg / ml to 20.0 mg / ml.

21. The high-concentration semaglutide liquid composition according to claim 18, wherein: The concentration of semaglutide ranged from 4 mg / ml to 15.0 mg / ml.

22. The high-concentration semaglutide liquid composition according to claim 18, wherein: The concentration of semaglutide is 4.5 mg / ml to 10.0 mg / ml.

23. The high-concentration semaglutide liquid composition according to claim 18, wherein: The concentration of semaglutide is 5.0 mg / ml to 10.0 mg / ml.

24. The high-concentration semaglutide liquid composition according to claim 18, wherein: The concentration of semaglutide was 5.5 mg / ml to 10.0 mg / ml.

25. The high-concentration semaglutide liquid composition according to claim 18, wherein: The concentration of semaglutide was 4.8 mg / ml to 6.0 mg / ml.

26. The high-concentration semaglutide liquid composition according to claim 18, wherein: The concentration of phenol is between 0.11% w / w and 0.5% w / w.

27. The high-concentration semaglutide liquid composition according to claim 18, wherein: The concentration of phenol is between 0.15% w / w and 0.4% w / w.

28. The high-concentration semaglutide liquid composition according to claim 18, wherein: The concentration of phenol is 0.2% w / w to 0.3% w / w.

29. The high-concentration semaglutide liquid composition according to claim 18, wherein: The concentration of phenol is 0.25% w / w to 0.35% w / w.

30. The high-concentration semaglutide liquid composition according to claim 18, wherein: The buffer is disodium hydrogen phosphate dihydrate.

31. The high-concentration semaglutide liquid composition according to claim 18, wherein: The pharmaceutically acceptable excipient is an isotonic agent selected from propylene glycol or sodium chloride.

32. The high-concentration semaglutide liquid composition according to claim 18, wherein: The composition is filled in multi-dose containers.

33. The high-concentration semaglutide liquid composition according to 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 semaglutide, wherein: The concentration of phenol is between 0.11% w / w and 0.5% w / w.

35. The multi-dose delivery device of claim 34, for delivering a liquid pharmaceutical composition of semaglutide, wherein: The concentration of semaglutide ranged from 3.0 mg / ml to 25.0 mg / ml.

36. A multi-dose delivery device according to claim 34, the device consisting of a cartridge of a liquid pharmaceutical composition suitable for delivering a plurality of variable doses of semaglutide.

37. The multi-dose delivery device of claim 34, for delivering a dose of semaglutide in the range of 0.25 mg to 2 mg for the treatment of diabetes.

38. The multi-dose delivery device of claim 34, for delivering a dose of semaglutide in the range of 0.25 mg to 2.4 mg for the treatment of obesity.

39. The multi-dose delivery device of claim 34, which is a reusable pen injector device.

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

41. The liquid pharmaceutical composition of semaglutide of claim 40, provided in a plurality of cartridges with a reusable pen injector.

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