FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
REUSABLE MULTI-DOSE, VARIABLE DOSE, SINGLE PEN INJECTOR FOR TYPE 2 DIABETES AND WEIGHT MANAGEMENT
2. APPLICANT(S):
a) NAME ZYDUS LIFESCTENCES LIMITED
b) NATIONALITY INDIAN
c) ADDRESS ZYDUS CORPORATE PARK, SCHEME NO. 63,
SURVEY NO. 536, KHORAJ (GANDHINAGAR), NR. VAISHNODEVI CIRCLE, AHMEDABAD, GANDHINAGAR, GUJARAT, INDIA, 382481
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it has to be performed.

Field of the invention
The present invention relates to a liquid pharmaceutical compositions of Semaglutide delivered with a reusable pen injector device. In an embodiment, the pen injector device comprises one or more cartridges suitable for delivering multiple 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 compositions comprising Semaglutide in 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 of the invention
Semaglutide is one of the useful drug for the treatment of type 2 diabetes and weight management. The drug is approved in an oral as well as injectable dosage form. WO2006097537 disclosed Semaglutide for the first time. The same document also disclosed certain injectable compositions of Semaglutide.
Semaglutide is a long-acting analogue of human glucagon like-1 peptide i.e. an Aib8, Arg34-GLP-1(7-37) analogue substituted on the ε-amino group of the lysine residue in position 26 with an (S)-22,40-dicarboxy-10,19,24-trioxo-3,6,12,15-tetraoxa-9,18,23-triazatetracontan-1-oyl side chain. The side chain consists of two 8-amino-3, 6-dioxaoctanoic acid (ADO) spacers, one γ-glutamic acid (Glu) spacer, and a fatty diacid (1, 18- octadecanedioic acid). Pharmaceutical dosage forms comprising Semaglutide are disclosed in WO 2006097537 and in WO 2019038412. There are two approved injectable brands of Semaglutide available. i.e. Ozempic® and Wegovy®.
Ozempic® is approved for treatment of diabetes and available in disposable pen injector and uses different device for different doses (Device 1: 0.25mg, 0.5mg; Device 2: 1mg; Device 3: 2mg). Ozempic® is available as a solution for subcutaneous injection wherein concentration of phenol is 5.5 mg/ml. Wegovy® is presented as a clear and colorless solution for subcutaneous injection in a 1 mL prefilled type I glass syringe (PFS) attached with stainless steel needle, rigid needle shield (type II/polyisoprene) and a rubber plunger (type I/chlorobutyl). The PFS is assembled into a single-use prefilled pen (PFP). Wegovy® is available with packs of 4 PFPs each: - 0.25 mg semaglutide in 0.5 mL (strength 0.25 mg); -0.5 mg semaglutide in 0.5 mL (strength 0.5 mg); 1 mg semaglutide in 0.5 mL
2

(strength 1 mg); - 1.7 mg semaglutide in 0.75 mL (strength 1.7 mg); - 2.4 mg Semaglutide in 0.75 mL (strength 2.4 mg).
One of the major drawback of the approved injectable (Wegovy®) Semaglutide formulations is that the injectable dosage form is available either in disposable single pen injectors or fixed dose, multiple dose injectors. So, a patient needs to use/buy disposable pen every week or need to buy different pen injector for different doses as per approved dosage regimen and for the entire time period of the therapy. The pen provided for injecting is a single use pen, and should be thrown out after each dose is administered. This not only increases the cost of therapy to the patient but also unnecessary waste is generated which has an impact on the environment also.
Further, as explained, in WO 2019038412, the Semaglutide liquid formulation is not stable when higher amount of phenol is used for formulating the higher dose of Semaglutide required for weight management therapy. Hence, the WO’412 document discloses formulations of Semaglutide with no or insignificant amounts of phenol. This typical formulation of Semaglutide probably necessitated the use of a single use pen for drug delivery.
Thus, it is required to research and develop a new formulation of Semaglutide that is more cost effective for patients, is stable enough to avoid use of single use pens for delivery, give better patient compliance and is environment friendly. Inventors of the present invention have surprisingly found that by optimizing the concentration of phenol in the formulation it is possible to formulate higher concentration of Semaglutide without impacting its stability. With such a stable formulation, it is possible to deliver multiple doses of Semaglutide using a multi-dose injector device containing a cartridge and the device can be reused by replacing with a new cartridge.
Thus the current invention aims to provide a high concentration formulations of Semaglutide with optimized phenol concentration which is stable and which can be delivered by a multi dose reusable pen.
Summary of the invention
3

The present disclosure relates to a high concentration Semaglutide liquid composition delivered with a reusable pen injector device. In an embodiment, the pen injector device comprises one or more cartridges suitable for delivering multiple doses of Semaglutide. The present invention also relates to certain liquid pharmaceutical compositions comprising Semaglutide is in concentration of 3 mg/mL to 25 mg/mL and phenol is in a concentration of 0.11% w/w to 0.5% w/w.
Embodiment of the invention
In an embodiment, the present invention provides a liquid pharmaceutical
compositions comprising Semaglutide and the phenol is in concentration of 0.11%
w/w to 0.5% w/w along with one or more pharmaceutically acceptable excipients.
In another embodiment, the present invention provides a liquid pharmaceutical
compositions comprising a high concentration Semaglutide and the phenol is in
concentration of 0.11% w/w to 0.5% w/w along with one or more pharmaceutically
acceptable excipients.
In another embodiment, the present invention provides a liquid pharmaceutical
compositions comprising Semaglutide is in concentration of 3 mg/mL to 25 mg/mL
and the phenol is in concentration of 0.11% w/w to 0.5% w/w along with one or
more pharmaceutically acceptable excipients.
In another embodiment, a liquid pharmaceutical compositions of the present
invention are for suitable for the treatment of type 2 diabetes, and for treatment of
obesity.
In another embodiment, the present invention provides a method for preparation of
a liquid pharmaceutical compositions comprising Semaglutide and the phenol is in
concentration of 0.11% w/w to 0.5% w/w along with one or more pharmaceutically
acceptable excipients.
In one of the embodiment, present invention provides a liquid pharmaceutical
compositions comprising Semaglutide and the phenol is in concentration of 0.11%
w/w to 0.5% w/w along with one or more pharmaceutically acceptable excipients
delivered using a reusable multi-dose drug delivery device.
In one of the embodiment, present invention provides a liquid pharmaceutical
compositions comprising Semaglutide and the phenol is in concentration of 0.11%
4

w/w to 0.5% w/w along with one or more pharmaceutically acceptable excipients delivered using a reusable pen injector device, wherein the pen injector is having a cartridge suitable for delivering multiple variable doses of Semaglutide. In another embodiment, the present invention provides a cartridge comprising a liquid pharmaceutical composition of Semaglutide wherein the concentration of Semaglutide is between 3 mg/mL to 25 mg/mL and the concentration of phenol is between 0.11% w/w to 0.5% w/w.
In one of the embodiment, present invention provides a liquid pharmaceutical compositions comprising Semaglutide delivered using a reusable pen injector device, wherein concentration of phenol in the formulation is about 0.11% w/w to 0.5% w/w. Further the pen injector is having a cartridge suitable for delivering multiple variable doses of Semaglutide.
Detailed description of the invention
The term ‘therapeutically effective amount’ or ‘therapeutic dose’ used anywhere in
the specification means amount of compound/ drug/ composition to treat disease
but low enough to avoid any serious side effects/toxicity/irritation or allergic
response.
The term ‘high concentration of Semaglutide’ means a formulation containing from
about 3 mg/ml to 25 mg/ml of Semaglutide.
The term ‘treatment’ used anywhere in the specification means prevention or
reduction or delay in progression of clinical symptoms of disease or disorder.
The term “RLD” means Reference Listed Drug.
The present invention relates to a liquid pharmaceutical composition comprising:
(a) Semaglutide;
(b) 0.11 % w/w to 0.5% w/w phenol;
(c) A buffer;
(d) One or more pharmaceutically acceptable excipients;
(e) Water.
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 yet another embodiment is disclosed a pharmaceutical composition of Semaglutide wherein the concentration of Semaglutide is about 3.5 mg/mL to 20.0 mg/mL. In yet another
5

embodiment is disclosed a pharmaceutical composition of Semaglutide wherein the concentration of Semaglutide is about 4 mg/mL to 15.0 mg/mL. In yet another embodiment is disclosed a pharmaceutical composition of Semaglutide wherein the concentration of Semaglutide is about 4.5 mg/mL to 10.0 mg/mL. In yet another embodiment is disclosed a pharmaceutical composition of Semaglutide wherein the concentration of Semaglutide is about 5 mg/mL to 10.0 mg/mL. In yet another embodiment is disclosed a pharmaceutical composition of Semaglutide wherein the concentration of Semaglutide is about 5.5 mg/mL to 10.0 mg/mL. It is to be understood that the range 3 mg/mL to about 25.0 mg/mL includes all intermediate ranges of concentration which are possible to be prepared by a skilled person. In a preferred embodiment is disclosed a pharmaceutical composition of Semaglutide wherein the concentration of Semaglutide is about 4.8 mg/mL to 6.0 mg/mL. 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 yet another embodiment is provided a pharmaceutical composition of Semaglutide wherein the concentration of phenol is about 0.15% w/w to 0.4% w/w. In yet another embodiment is provided a pharmaceutical composition of Semaglutide wherein the concentration of phenol is about 0.2% w/w to 0.3% w/w. It is to be understood that the range 0.11% w/w to 0.5% w/w includes all intermediate ranges of concentration which are possible to be prepared by a skilled person. In a preferred embodiment is provided a pharmaceutical composition of Semaglutide wherein the concentration of phenol is about 0.25% w/w to 0.35% w/w.
A liquid pharmaceutical composition of Semaglutide as disclosed above wherein a buffer, such as phosphate buffer, TRIS, citrate, or no buffer. In some embodiments the phosphate buffer is preferred and such phosphate buffer is a sodium phosphate buffer, such as disodium phosphate dihydrate.
The concentration of buffer used is about 0.5 mg/mL to about 1.5 mg/mL. In yet another embodiment, a pharmaceutical composition of Semaglutide is provided wherein the concentration of buffer is about 0.5 mg/mL to 1.0 mg/mL. In yet another embodiment, a pharmaceutical composition of Semaglutide is provided wherein the concentration of buffer is about 1 mg/mL to 1.5 mg/mL. In a preferred
6

embodiment, the concentration of the buffer in the pharmaceutical composition is
about 1.4 mg/mL to 1.5 mg/mL.
One or more pharmaceutically acceptable excipients is an isotonic agent. The
isotonic agent is propylene glycol or sodium chloride.
In preferred embodiments, the isotonic agent is propylene glycol.
The concentration of isotonic agent is about 1 mg/mL to about 20 mg/mL. In yet
another embodiment, a pharmaceutical composition of Semaglutide is provided
wherein the concentration of isotonic agent is about 4 mg/mL to 16 mg/mL. In yet
another embodiment, a pharmaceutical composition of Semaglutide is provided
wherein the concentration of 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.
The composition of the invention has a pH in the range of 3-10, such as pH 6-10 or
6-9 and all intermediate possible values of pH. In some embodiments the
composition of the invention has a pH in the range of pH 6.5-8.5, more preferably
a pH of 7.0-7.8.
A volume of the water to be added is to bring the total volume of composition to 1
mL or desire volume.
The composition of the invention is for parenteral administration. In some
embodiments the composition is for subcutaneous administration.
In another embodiment, a liquid pharmaceutical composition of Semaglutide of the
present invention is filled into a multi-dose container.
In some embodiments, a liquid pharmaceutical composition of Semaglutide of the
invention are for suitable for the treatment type 2 diabetes, and for treatment of
obesity.
In another embodiment, provides a process for the preparation of a liquid
pharmaceutical composition of Semaglutide of the present invention as described
below:
1. Initially, water for injection (WFI) was collected at 80% of target batch size and dissolved oxygen of WFI was controlled at less than 2ppm;
2. Suitable buffer was added in step 1 WFI and stirred to dissolve;
3. Phenol was added in step 1 solution and stirred to dissolve;
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4. Suitable isotonic agent was added in step 1 solution and stirred to dissolve;
5. Semaglutide was added in step 1 solution and stirred to dissolve;
6. pH of above solution was adjusted to pH 7.4 using 0.5%w/v sodium hydroxide and/or 0.5%w/v hydrochloric acid;
7. Volume make up to target batch size was done using the WFI ;.
8. Bulk was filtered through a 0.22 µ filter and was filled in 3 mL cartridges.
The composition of the invention is for parenteral administration. In some
embodiments the composition is for subcutaneous administration.
It has surprisingly been found that when a concentration from about 0.11 % w/w to 0.5% w/w of phenol is used helps to stabilize a liquid pharmaceutical composition of the present invention.
In a preferred embodiment, a stable liquid pharmaceutical composition of the invention comprises 4.8 mg/mL Semaglutide, 0.35% w/w phenol, 1.42 mg disodium phosphate dihydrate, 14 mg/mL propylene glycol and water. The present invention relates to a high concentration Semaglutide liquid composition delivered with a reusable pen injector device.
In an embodiment, the invention comprises a liquid pharmaceutical composition of Semaglutide wherein the concentration of Semaglutide is about 3.0 mg/mL to about 25.0 mg/mL. In yet another embodiment is disclosed a pharmaceutical composition of Semaglutide wherein the concentration of Semaglutide is about 3.5 mg/mL to 20.0 mg/mL. In yet another embodiment is disclosed a pharmaceutical composition of Semaglutide wherein the concentration of Semaglutide is about 4 mg/mL to 15.0 mg/mL. In yet another embodiment is disclosed a pharmaceutical composition of Semaglutide wherein the concentration of Semaglutide is about 4.5 mg/mL to 10.0 mg/mL. In yet another embodiment is disclosed a pharmaceutical composition of Semaglutide wherein the concentration of Semaglutide is about 5 mg/mL to 10.0 mg/mL. In yet another embodiment is disclosed a pharmaceutical composition of Semaglutide wherein the concentration of Semaglutide is about 5.5 mg/mL to 10.0 mg/mL. It is to be understood that the range 3 mg/mL to about 25.0 mg/mL includes all intermediate ranges of concentration which are possible to be prepared by a skilled person. In a preferred embodiment is disclosed a pharmaceutical
8

composition of Semaglutide wherein the concentration of Semaglutide is about 4.8
mg/mL to 6.0 mg/mL.
Further high concentration Semaglutide liquid composition wherein the
concentration of phenol is about 0.11% w/w to 0.5% w/w. In yet another
embodiment is provided a pharmaceutical composition of Semaglutide wherein the
concentration of phenol is about 0.15% w/w to 0.4% w/w. In yet another
embodiment is provided a pharmaceutical composition of Semaglutide wherein the
concentration of phenol is about 0.2% w/w to 0.3% w/w. It is to be understood that
the range 0.11% w/w to 0.5% w/w includes all intermediate ranges of concentration
which are possible to be prepared by a skilled person. In a preferred embodiment is
provided a pharmaceutical composition of Semaglutide wherein the concentration
of phenol is about 0.25% w/w to 0.35% w/w.
A high concentration Semaglutide liquid composition further comprises a buffer,
such as phosphate buffer, TRIS, citrate, or no buffer. In some embodiments the
phosphate buffer is preferred and such phosphate buffer is a sodium phosphate
buffer, such as disodium phosphate dihydrate.
A high concentration Semaglutide liquid composition wherein the concentration of
buffer is about 0.5 mg/mL to about 1.5 mg/mL. In yet another embodiment, a
pharmaceutical composition of Semaglutide is provided wherein the concentration
of buffer is about 0.5 mg/mL to 1.0 mg/mL. In yet another embodiment, a
pharmaceutical composition of Semaglutide is provided wherein the concentration
of 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.
A high concentration Semaglutide liquid composition further comprises one or
more pharmaceutically acceptable excipients.
A high concentration Semaglutide liquid composition comprises an isotonic agent.
In some embodiments the isotonic agent is propylene glycol or sodium chloride.
In preferred embodiments, the isotonic agent is propylene glycol.
A high concentration Semaglutide liquid composition wherein the concentration of
isotonic agent is about 1 mg/mL to about 20 mg/mL. In yet another embodiment, a
pharmaceutical composition of Semaglutide is provided wherein the concentration
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of isotonic agent is about 4 mg/mL to 16 mg/mL. In yet another embodiment, a pharmaceutical composition of Semaglutide is provided wherein the concentration of 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.
A high concentration Semaglutide liquid compositioncomprises water wherein volume of the water to be added is to bring the total volume of composition to 1 mL or desire volume.
A high concentration Semaglutide liquid composition has a pH in the range of 3-10, such as pH 6-10 or 6-9 and all intermediate possible values of pH. In some embodiments the composition of the invention has a pH in the range of pH 6.5-8.5, more preferably a pH of 7.0-7.8.
The composition of the invention is for parenteral administration. In some embodiments the composition is for subcutaneous administration. In another embodiment, a high concentration Semaglutide liquid composition of the present invention is filled into a multi-dose container.
In some embodiments, a high concentration Semaglutide liquid composition of the invention are for suitable for the treatment type 2 diabetes and for treatment of obesity.
It has surprisingly been found that when a concentration from about 0.11 % w/w to 0.5% w/w of phenol is used, it is possible to stabilize high concentration of Semaglutide.
In one of the embodiment, present invention provides a multi-dose delivery device to deliver a liquid pharmaceutical composition of Semaglutide wherein concentration of phenol is 0.11% w/w to 0.5% w/w.
A multi-dose delivery device to deliver a liquid pharmaceutical composition of Semaglutide wherein concentration of Semaglutide is 3.0 mg/ml to 25.0 mg/ml. In one of the embodiment, present invention provides a liquid pharmaceutical composition of Semaglutide delivered using a reusable multi-dose drug delivery device wherein concentration of Semaglutide is 3.0 mg/mL to 25.0 mg/mL and concentration of phenol is 0.11% w/w to 0.5% w/w.
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In one of the embodiment, present invention provides a liquid pharmaceutical
composition of Semaglutide delivered using a reusable pen injector device, wherein
the pen injector is having a cartridge suitable for delivering multiple variable doses
of a liquid pharmaceutical composition of Semaglutide.
In some embodiments, the present invention provides a liquid pharmaceutical
composition of Semaglutide in a multi-dose drug delivery device suitable for
administering from 0.25 mg dose of Semaglutide to 2.4 mg of Semaglutide through
a single device to a patient for treatment type 2 diabetes, and obesity.
In some embodiments the present invention provides a liquid pharmaceutical
composition of Semaglutide in a multi-dose drug delivery device suitable for
administering from 0.25 mg dose of Semaglutide to 2 mg of Semaglutide through
a single device to a patient for treatment type 2 diabetes.
In some embodiments the present invention provides a liquid pharmaceutical
composition of Semaglutide in a multi-dose drug delivery device suitable for
administering from 0.25 mg dose of Semaglutide to 2.4 mg of Semaglutide through
a single device to a patient for obesity.
In an embodiment, the multi-dose drug delivery device is a reusable pen injector.
In another embodiment, the present invention provides a cartridge comprising a
liquid pharmaceutical composition of Semaglutide wherein the concentration of
Semaglutide is between 3 mg/ml to 25 mg/ml and the concentration of phenol is
between 0.11% w/w to 0.5% w/w with buffer, pharmaceutically acceptable
excipients as disclosed anywhere in the specification and water.
A liquid pharmaceutical composition of Semaglutide as per the present invention is
provided in multiple cartridges with the reusable pen injector.
Device:
The reusable pen injector:
Multiple cartridges will be supplied with the reusable pen injector. Once the required number of doses from a single cartridge is 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 as per the treatment requirement. The user steps will mainly involve priming the pen, dialing a target dose and injecting the dose at target injection site.
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In one of the embodiment, the present invention provides a high concentration Semaglutide liquid composition delivered using a reusable pen injector device, wherein the pen injector containing a cartridge suitable for delivering multiple doses of Semaglutide as per the therapy needs of a patient.
Further Semaglutide is sensitive to sunlight and degrade by exposer of direct sunlight. So to protect the Semaglutide from direct sunlight, cartridge is prepared with suitable material or packed in blister pack.
In addition to the reusable feature, the proposed pen injector will also be able to deliver variable doses. This will allow delivering multiple numbers of doses as per the dosage schedule necessary for weight management and type 2 diabetes treatment. The details of the representative number of doses which can be delivered once loaded for e.g. in a 3mL filled cartridge is presented in below table.
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Table 1: Number of doses per device device

different Semaglutide concentration per

No of doses/cartridge (having
fill 3mL) at concentration
4mg/mL
0.25mg (4 doses),
14 0.5mg
doses/cartridge (4 doses),
For weight management 1mg
(4 doses) &
1.7mg
(2 doses)

5 2.4mg
doses/cartridge (5 doses)
0.25mg (4 doses), 0.5mg
For diabetes 14 doses/cartridge (4 doses), 1mg
(4 doses) & 2mg (2 doses)

No of doses/cartridge (having fill 3mL) at concentration 4.8mg/mL No of doses/cartridge (having fill 3mL) at concentration 25mg/mL
16
doses/ca
rtridge 0.25mg
(4 doses),
0.5mg
(4 doses),
1mg
(4 doses)
&
1.7mg
(4 doses) 40
doses/cartri
dge 0.25mg
(4 doses),
0.5mg
(4 doses),
1mg
(4 doses)
&
1.7mg
(4 doses)
6
doses/ca
rtridge 2.4mg (6 doses)
2.4mg (24 doses)
15
doses/ca
rtridge 0.25mg (4 doses), 0.5mg (4 doses), 1mg
(4 doses) &
2mg (3 doses) 46
doses/cartri
dge 0.25mg (4 doses), 0.5mg (4 doses), 1mg
(4 doses) &
2mg (34 doses)
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Table 2: RLD device vs Device used in Present invention)-For Type 2 Diabetes

RLD Device (Brand: Ozempic) Device use in present invention
• Multi-dose (Different device
for Different doses); Total 3
different devices (Device 1:
0.25mg;0.5mg, Device 2: 1mg,
Device 3: 2mg)
• Disposable device (Pen
injector) • Multi-Dose, Same Device for
Multiple Doses (Approx. 15
Doses from 1 Device/Cartridge
for 0.25, 0.5, 1 & 2 mg doses)
• Reusable device with new
cartridge again
•
Different device for different dose Same device for different multiple doses
Mellitus
Table 3: RLD device vs Device used in Present invention)-For Weight
management

RLD Device (Brand: Wegovy) Device use in present invention
• Single dose, fixed
dose (1 Dose from
1 Device; Total 5
different devices)
• Disposable device
(Auto Injector) • Multi-Dose, Variable dose (Approx.16
Doses from 1 Device/Cartridge for 0.25,
0.5, 1 &1.7mg doses and 6 doses from 1
Device/Cartridge for 2.4mg Dose); Same
device for multiple doses
• Reusable device with new cartridge again
•
Different device for different dose Same device for different multiple doses
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One advantage of the pen injector is that it is provided with a mechanism that can reliably deliver a medicament with multiple dose via a single pen injector. Same device is able to deliver different doses for type 2 diabetes treatment as well as for weight management, in approved dosage form it can be delivered by different device.
Another advantage is that a pen injector is provided with a mechanism that will never deliver a volume of medicament larger than what the patient selected. Still another advantage is that a pen cap can be provided with a cartridge which may be changed and the pen injector can be reused for the drug delivery again and patient need not to buy new pen injector every time he wants a refill making the current invention cost effective also.
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Table 4: Semaglutide composition in multi-dose reusable pen injector as per present invention. (Weight management)
Currently approved product is single dose disposable auto injector (Each device can deliver only one dose)
Minimum no of doses
required
Proposed
Bulk
conc,
mg/mL
Total drug
for
delivering
target
doses
Fill
volume,
mL
Weekly dose
Proposed Strength
Proposed no of
Week
Dose type
doses to be delivered from single cartridge
4 doses
of
0.25mg
(Total:
1mg)
1
through
4
1 mg eq to 4 doses
4 doses (1mg) or
0.25 mg
more
(additional
4), Total: 8
doses
4 doses
of 0.5mg (Total: 2mg)
5
through
8
2 mg eq to 4 doses
4 doses (2mg) or
0.5 mg
more
16 doses/
Cartridge/
Reusable
device
(additional
Dose Escalation
14.4 mg/ 3mL
4), Total: 8
4.8
3
doses
4 doses
of 1 mg
(Total:
4mg)
9
through
12
4 mg eq to 4 doses
4 doses (4mg) or
1 mg
more
(additional
4), Total: 8
doses
4 doses of 1.7
mg (Total: 6.8mg)
13
through
16
6.8 mg eq to 4 doses
4 doses
2 mg
(6.8mg)
or more
(additional
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Week 17 and onward 2.4 mg 4), Total: 8 doses 4.8 3 14.4 mg/ 3mL 6 doses of 2.4
mg
(Total:
14.4mg)

Maintenance dose Long term treatment


6 doses/
Cartridge/
Reusable
Device

Table 5: Semaglutide composition in Multi-dose reusable pen injector as per present invention (Type 2 Diabetes)
Currently approved product is a multi-dose disposable pen injector but uses different device for different doses (Device 1: 0.25mg, 0.5mg; Device 2: 1mg; Device 3: 2mg)

Week
First 4 weeks
After 4
weeks
of
0.25
mg
After 4
weeks
of
0.5 mg Weekl y dose
0.25 mg
0.5 mg 1 mg Minimu m no of doses required Total drug for deliverin g target doses Bulk conc, mg/m L
4.8 Fill volum e, mL
3 Strengt h
14.4
mg/ 3
mL No of doses to be delivered from single cartridge

4 doses (1 mg) 1 mg eq to 4 doses


15 doses/ Cartridge/ Reusable device 4 doses of 0.25 mg (Total: 1 mg)

4 doses (2 mg) 2 mg eq to 4 doses



4 doses of 0.5 mg (Total: 2 mg)

4 doses (4 mg) 4 mg eq to 4 doses



4 doses of 1
mg
(Total: 4 mg)
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After 4 weeks of 1 mg 2 mg 4 doses (8 mg) 8 mg eq to 4 doses 3 doses of 2
mg
(Total: 6 mg)
The present invention thus relates to multi-dose reusable pen injector to deliver different doses from single device and suitable for the effective treatment of both, type 2 diabetes and for weight management therapy. Each device can deliver different doses as per the dosage regimens necessary for effective of type 2 diabetes therapy and weight management. From a single cartridge/device, it is possible to provide effective dosages from 0.25 mg dose of Semaglutide to 2.4 mg of Semaglutide through a single device to a patient. Thus, it is possible to provide multiple doses such as 0.25 mg/0.5 mg/1 mg/1.7 mg/2 mg /2.4 mg to a patient in need thereof. This will reduce significant cost to patient. The Pen device can also be reused multiple times with new cartridge to deliver required no of doses.
Advantage of the present invention over existing therapy are
• High concentration, stable formulations of Semaglutide.
• Multiple doses of variable different doses can be delivered from a single device.
• Device can be reused by replacing with a new cartridge.
• Cost effective option for patients.
• Better patient compliance though adherence to long term treatment.
Following are non-limiting examples of high concentration, stable formulations of
Semaglutide. It is illustrative and representing the preferred modes of carrying out
the invention. The scope of invention is not limited to these specific embodiments
only but should be read in conjunction with what is disclosed anywhere else in the
specification together with those information and knowledge that are within the
general understanding of a person skilled in the art.
• Examples
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Example 1:

S. No. Ingredient Quantity
1 2 3 4 5 6 7 Semaglutide 4.8 mg/mL

Disodium phosphate dihydrate 1.42 mg/mL

Propylene glycol 14 mg/mL

Phenol 1.5 mg/mL

Sodium hydroxide q.s. to pH 7.4

Hydrochloric Acid q.s. to pH 7.4

Water for Injection q.s. to batch size
q.s. quantity sufficient
Manufacturing procedure:
1. Initially, water for injection (WFI) was collected at 80% of target batch size and dissolved oxygen of WFI was controlled at less than 2ppm.
2. Disodium phosphate dihydrate was added in step 1 WFI and stirred to dissolve.
3. Phenol was added in step 1 solution and stirred to dissolve.
4. Propylene glycol was added in step 1 solution and stirred to dissolve.
5. Semaglutide was added in step 1 solution and stirred to dissolve.
6. pH of 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, volume make up to target batch size was done using the WFI and if required, dissolved oxygen of WFI was controlled at less than 2ppm.
8. Bulk was filtered through a 0.22 µ filter and was filled in 3 mL cartridges.
Stability study of composition of Example 1 has been carried out on same day of
the preparation and after 1 week. Composition of Example 1 were kept in Glass
Vials at 2-8 °C, at 25 °C and 60% relative humidity, at 40 °C and 75% relative
humidity for stability study.
19

Stability study of Example 1

Tests Initial 2-8°C 25°C/60%RH 40°C/75%RH 1 week 1 week 1 week
Description Clear
and
colorless
solution Clear and colorless solution Clear and colorless solution Clear and colorless solution
% Assay Semaglutide (By HPLC) 99.0 100.7 97.7 97.7
Osmolarity 236.0 233 233 236
pH 7.44 7.46 7.45 7.45
Transmittance 99.5 98.8 98.6 99.5
% Absorbance 0.001 0.004 0.003 0.004
Aggregation 0.23 0.23 0.24 0.25
Related Substance Any
unspecified degradation product ND ND ND ND

Total
degradation
products 1.4 1.5 1.5 2.3
Example 2:

S. No. Ingredient Quantity
1 2 3 4 5 6 7 Semaglutide 4.8 mg/mL

Disodium phosphate dihydrate 1.42 mg/mL

Propylene glycol 14 mg/mL

Phenol 3.5 mg/mL

Sodium hydroxide q.s. to pH 7.4

Hydrochloric Acid q.s. to pH 7.4

Water for Injection q.s. to batch size
q.s. quantity sufficient
Manufacturing procedure:
20

1. Initially, water for injection (WFI) was collected at 80% of target batch size and dissolved oxygen of WFI was controlled at less than 2ppm.
2. Disodium phosphate dihydrate was added in step 1 WFI and stirred to dissolve.
3. Phenol was added in step 1 solution and stirred to dissolve.
4. Propylene glycol was added in step 1 solution and stirred to dissolve.
5. Semaglutide was added in step 1 solution and stirred to dissolve.
6. pH of 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, volume make up to target batch size was done using the WFI and if required, dissolved oxygen of WFI was controlled at less than 2ppm.
8. Bulk was filtered through a 0.22 µ filter and was filled in 3 mL cartridges.
Stability study of composition of Example 2 has been carried out on same day of
the preparation and after 1 week. Composition of Example 2 were kept in Glass
Vials at 2-8 °C, at 25 °C and 60% relative humidity, at 40 °C and 75% relative
humidity for stability study.
Stability study of Example 2

Tests Initial 2-8°C 1 week 25°C/60%RH 1 week 40°C/75%RH 1 week
Description Clear
and
colorless
solution Clear and colorless solution Clear and colorless solution Clear and colorless solution
% Assay Semaglutide (By HPLC) 99.6 99.5 100.6 97.6
Osmolarity 263.0 262 261 263
pH 7.50 7.35 7.34 7.36
Transmittance 99.5 99.8 99.7 99.7
% Absorbance 0.002 0.003 0.003 0.004
Aggregation 0.23 0.23 0.25 0.27
21

Related Any ND ND ND ND
Substance unspecified degradation product

Total 1.7 1.8 1.8 2.5
degradation products
Example 3:

S.No. Ingredient Quantity
1 Semaglutide 4.8 mg/mL
2 Di sodium phosphate dihydrate 1.42mg/mL
3 Propylene glycol 14 mg/mL
4 Phenol 5 mg/mL
5 Sodium hydroxide q.s. topH7.4
6 Hydrochloric Acid q.s. topH7.4
7 Water for Injection q.s. to batch size
q.s. quantity sufficient
Manufacturing procedure:
1. Initially, water for injection (WFI) was collected at 80% of target batch size and dissolved oxygen of WFI was controlled at less than 2ppm.
2. Di sodium phosphate dihydrate was added in step 1 WFI and stirred to dissolve.
3. Phenol was added in step 1 solution and stirred to dissolve.
4. Propylene glycol was added in step 1 solution and stirred to dissolve.
5. Semaglutide was added in step 1 solution and stirred to dissolve.
6. pH of 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, volume make up to target batch size was done using the WFI and if required, dissolved oxygen of WFI was controlled at less than 2ppm.
8. Bulk was filtered through a 0.22 u filter and was filled in 3 mL cartridges.

Stability study of composition of Example 3 has been carried out on same day of the preparation and after 1 week. Composition of Example 3 were kept in Glass Vials at 2-8 °C, at 25 °C and 60% relative humidity, at 40 °C and 75% relative
humidity for stability study. Stability study of Example 3

Tests Initial 2-8°C 1 week 25°C/60%RH 1 week 40°C/75%RH 1 week
Description Clear
and
colorless
solution Clear and colorless solution Clear and colorless solution Clear and colorless solution
% Assay Semaglutide (By HPLC) 100.6 100.0 100.5 97.4
Osmolarity 268.0 269 261 270
pH 7.45 7.38 7.41 7.44
Transmittance 99.5 99.4 99.6 99.1
% Absorbance 0.003 0.003 0.003 0.004
Aggregation 0.22 0.23 0.25 0.28
Related Substance Any
unspecified degradation product ND ND ND ND

Total
degradation
products 1.5 1.6 1.6 2.5

We claim:
1. A liquid pharmaceutical composition comprising:
(a) Semaglutide;
(b) 0.11 % w/w to 0.5% w/w phenol;
(c) A buffer;
(d) One or more pharmaceutically acceptable excipients;
(e) Water.

2. A liquid pharmaceutical composition as claimed in claim 1 wherein Semaglutide is in concentration of 4.8 mg/ml to 6.0 mg/ml.
3. A liquid pharmaceutical composition as claimed in claim 1 wherein phenol is in concentration of 0.15% w/w to 0.4% w/w.
4. A liquid pharmaceutical composition as claimed in claim 1 wherein phenol is in concentration of 0.2% w/w to 0.3% w/w.
5. A liquid pharmaceutical composition as claimed in claim 1 wherein phenol is in concentration of 0.25% w/w to 0.35% w/w.
6. A liquid pharmaceutical composition as claimed in claim 1 wherein buffer is disodium phosphate dihydrate.
7. A liquid pharmaceutical composition as claimed in claim 1 wherein
pharmaceutically acceptable excipient is isotonic agent selected from propylene
glycol or sodium chloride.
8. The liquid pharmaceutical composition as claimed in claim 1, wherein said composition is filled into a multi-dose container.
9. The liquid pharmaceutical composition as claimed in claim 1, wherein said pharmaceutical composition is useful for treating diabetes and obesity.

10. A liquid pharmaceutical composition comprising 4.8 mg/mL Semaglutide,
0.35% w/w phenol, 1.42 mg disodium phosphate dihydrate, 14 mg propylene glycol
and water.
11. A high concentration Semaglutide liquid composition delivered with a reusable pen injector device.
12. A high concentration Semaglutide liquid composition as claimed in claim 11 wherein Semaglutide is in concentration of 3.0 mg/ml to 25.0 mg/ml.
13. A high concentration Semaglutide liquid composition as claimed in claim 11 wherein Semaglutide is in concentration of 3.5 mg/ml to 20.0 mg/ml.
14. A high concentration Semaglutide liquid composition as claimed in claim 11 wherein Semaglutide is in concentration of 4 mg/ml to 15.0 mg/ml.
15. A high concentration Semaglutide liquid composition as claimed in claim 11 wherein Semaglutide is in concentration of 4.5 mg/ml to 10.0 mg/ml.

16. A high concentration Semaglutide liquid composition as claimed in claim 11wherein Semaglutide is in concentration of 5.0 mg/ml to 10.0 mg/ml.
17. A high concentration Semaglutide liquid composition as claimed in claim 11 wherein Semaglutide is in concentration of 5.5 mg/ml to 10.0 mg/ml.
18. A high concentration Semaglutide liquid composition as claimed in claim 11 wherein Semaglutide is in concentration of 4.8 mg/ml to 6.0 mg/ml.
19. A high concentration Semaglutide liquid composition as claimed in claim 11 wherein phenol is in concentration of 0.11% w/w to 0.5% w/w.
20. A high concentration Semaglutide liquid composition as claimed in claim 11 wherein phenol is in concentration of 0.15% w/w to 0.4% w/w.
21. A high concentration Semaglutide liquid composition as claimed in claim 11 wherein phenol is in concentration of 0.2% w/w to 0.3% w/w.
22. A high concentration Semaglutide liquid composition as claimed in claim 11 wherein phenol is in concentration of 0.25% w/w to 0.35% w/w.

23. A high concentration Semaglutide liquid composition as claimed in claim 11 wherein buffer is disodium phosphate dihydrate.
24. A high concentration Semaglutide liquid composition as claimed in claim 11 wherein pharmaceutically acceptable excipient is isotonic agent selected from propylene glycol or Sodium chloride.
25. A high concentration Semaglutide liquid composition as claimed in claim 11 wherein said composition is filled into a multi-dose container.
26. A high concentration Semaglutide liquid composition as claimed in claim 11 wherein said pharmaceutical composition is useful for treating diabetes and obesity.
27. A multi-dose delivery device to deliver a liquid pharmaceutical composition of Semaglutide wherein concentration of phenol is 0.11% w/w to 0.5% w/w.
28. A multi-dose delivery device as claimed in claim 27 is a reusable pen injector device.
29. A cartridge comprising a liquid pharmaceutical composition of Semaglutide wherein Semaglutide in concentration of 3 mg/ml to 25 mg/ml and the phenol in concentration of 0.11% w/w to 0.5% w/w with buffer, pharmaceutically acceptable excipients and water.
30. A liquid pharmaceutical composition of Semaglutide as claimed in claim 29 provided in multiple cartridges with the reusable pen injector.