WO2021123228A1 - Pharmaceutical composition comprising glp-1 analogue - Google Patents
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Abstract
The present invention discloses new pharmaceutical compositions containing a Glucagon-like peptide-1 (GLP-1) analogue optionally in a combination with one or more other active substances. The present invention further provides methods for making the same.
Description
Pharmaceutical composition comprising GLP-1 analogue
1. Technical field of the invention
The present invention pertains to new pharmaceutical compositions containing a Glucagon like peptide- 1 (GLP-1) analogue. In particular, the present invention provides pharmaceutical compositions containing one or more GLP-1 analogues such as liraglutide and semaglutide, optionally in a combination with one or more other active substances. The pharmaceutical compositions according to the present invention are physically and chemically stable, are easy to manufacture and suitable for parenteral administration. The present invention further provides methods for making the same.
2. Background of the invention
It is a well-known fact that GLP-1 analogues are useful in many different fields. They are widely used in medicine to control insulin levels and digestion, to improve glucose control in adults with type 2 diabetes mellitus, as well as to treat obesity, sleep apnoea and diabetic complications, such as angiopathy, neuropathy and retinopathy. Additionally, growing evidence suggest that GLP-1 analogues can be used to prevent or treat cardiovascular complications and neurodegenerative diseases.
Glucagon-like peptide- 1 (GLP-1) is a 30 amino acid long peptide hormone deriving from the tissue-specific posttranslational processing of the proglucagon gene. It is produced and secreted by intestinal enteroendocrine L-cells and certain neurons within the nucleus of the solitary tract in the brainstem upon food consumption. The initial product GLP-l(l-37) is susceptible to amidation and proteolytic cleavage which gives rise to the two truncated and equipotent biologically active forms, GLP-1 (7-36) amide and GLP-1 (7-37). Active GLP-1 composes two a-helices from amino acid position 13-20 and 24-35 separated by a linker region.
Liraglutide, Arg34, Lys26(N-s(y-Glu(N-ahexadecanoyl)))-GLP-l (7-37), is a long acting analogue of the naturally occurring human glucagon-like peptide-1 (GLP-l(7-37)). Liraglutide has a substitution of the naturally occurring amino acid residue in position 34
(Lys) by Arg and addition of a Glu-spaced hexadecanoic acid (palmitic acid) to the e-amino group of Lys in position 26. It is a derivative of a human incretin, glucagon-like peptide- 1 (GLP-1) that is used as a long-acting glucagon-like peptide- 1 receptor agonist, binding to the same receptors as does the endogenous metabolic hormone GLP-1 that stimulates insulin secretion. It is developed and marketed as Victoza by Novo Nordisk for the treatment of type 2 diabetes and under the brand name Saxenda, again by Novo Nordisk, for obese or overweight adults. Liraglutide is marketed under brand name VICTOZA® and SAXENDA® in the United States.
Semaglutide, N-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoyl amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]-GLP-l (7-37), is a long-acting once-weekly human GLP-1 analogue, marketed as Ozempic by Novo Nordisk for the treatment of Type 2 diabetes. The main protraction mechanism of semaglutide is albumin binding, facilitated by modification of position 26 lysine with a hydrophilic spacer and a Cl 8 fatty di-acid. Semaglutide is modified in position 8 to provide stabilization against degradation by the enzyme dipeptidyl-peptidase 4. A minor modification was made in position 34 to ensure the attachment of only one fatty di-acid. Semaglutide is marketed under brand name OZEMPIC® in the United States.
Prior art documents already provided some compositions of GLP-1 analogues.
W02003002136 discloses isotonic composition comprising GLP-l(7-37) analogue in a concentration from 0.1 mg/ml to 100 mg/ml, a buffer, an isotonic agent and a preservative wherein the composition has a pH of 7.0 to 10.
W02004105781 discloses composition comprising specific buffers and specific preservatives wherein GLP-1 analogue is prepared by freeze-drying and the pH of composition is lower than the pH of bulk peptide.
A method for increasing the shelf-life of a pharmaceutical composition which comprises a glucagon-like peptide, a pharmaceutically acceptable buffer and a pharmaceutically acceptable preservative, characterized in that said pharmaceutical composition is prepared from a bulk peptide product which has been produced by drying a solution or suspension of said glucagon-like peptide having a pH above 8.0 is disclosed in W02004105790.
W02005049061 discloses propylene glycol containing peptide compositions for use in injection devices. The document teaches that by using propylene glycol at concentrations of 1-100 mg/ml the reduction of deposits in production equipment and in the final product and reducing clogging of injection devices is observed.
EP2494983B1 describes the method for preparation of a stable solution of a GLP-l(7-37) (SEQ ID NO. 1), insulinotropic analogue thereof and insulinotropic derivatives thereof, which method comprises heating a solution of said GLP-l(7-37), wherein the temperature is between 50° C and 85 °C, the pH is between 8.0 to 10.5 and the heating is continued for a period of time which is between 3 minutes and 180 minutes.
WO2007146448 describes intranasal compositions ofGLP-1 compounds.
CN102429876 and CN110368376 describe sustained release microsphere liraglutide preparation.
CN110339166 discloses polycystic liposome comprising liraglutide, membrane material, osmotic pressure regulator and stabilizer.
A pharmaceutical composition comprising liraglutide, a buffer selected from the group consisting of dipotassium phosphate, sodium bicarbonate, and disodium phosphate anhydrous; propylene glycol and a preservative is disclosed in WO2016038521.
Pharmaceutical composition comprising liraglutide wherein manufacturing process comprising mixing liraglutide and adjuvant in a solvent, stirring at 500-1 lOOrpm until homogeneous mixture is obtained and pH is adjusted to 7.5-9.5 is disclosed in WO2017147783.
WO20 18096460 discloses liraglutide composition comprising specific buffers, specific isotonic agents and specific preservatives.
Pharmaceutical compositions for the transmucosal delivery of therapeutic peptides and proteins comprising an excipient with pKa value of 12 or higher, such as arginine free base,
EDTA tetrasodium salt, trisodium phosphate, tris(hydroxymethyl)aminomethane, lysine, and calcium hydroxide, are disclosed in WO2019193204.
WO2019110837 discloses a composition in the form of an injectable aqueous solution including human glucagon and a co-polyaminoacid.
However, for various reasons, there remains a need for alternative pharmaceutical compositions exhibiting a desired physical and chemical stability. The present invention has been completed based on these findings.
3. Summary of the invention
The present invention pertains to new pharmaceutical compositions containing a Glucagon like peptide- 1 (GLP-1) analogue. In particular, the present invention provides pharmaceutical compositions containing one or more GLP-1 analogues such as liraglutide and semaglutide, optionally in a combination with one or more other active substances and methods for making the same as specified in the appended claims. Specifically, the present invention provides pharmaceutical compositions containing liraglutide or semaglutide as the active ingredient and propylene glycol as the tonicity agent wherein the active ingredient solution is treated at temperature between 26 and 49°C.
Drawings
Figure 1: Fibrillation tendency of formulations with the liraglutide active ingredient solution treated at temperature 35°C, 70°C for 1 hour, 2 hours, 6 hours
4. Detailed description
The pharmaceutical composition of the present invention comprises a GLP-1 analogue, a buffering agent, a tonicity agent, a preservative and optionally other pharmaceutically acceptable excipients selected from the group consisting of but not limited to one or more solvents, one or more chelating agents, one or more stabilisers, pH adjusting agents, antioxidants and surfactants. The pharmaceutical composition of the present invention may comprise in addition to at least one GLP-1 analogue at least one other active substance. The
pharmaceutical composition of the present invention is in the form of a solution, more particularly in the form of an injectable solution.
Temperature treatment of a peptide solution has been suggested in the literature, especially in EP 2 494 983 A as cited above, as a possible means for the improvement of the physico chemical stability of peptides, mainly with regards to the tendency for fibre formation. However, there is still a need for further improvement of the stabilization treatment. The present inventors have surprisingly found that suitably choosing the treatment conditions allows to further reduce the tendency for aggregate formation. The accomplishment of this objective is hampered by the need to maintain excellent performance characteristics with respect to stability and the like. The present inventors have found suitable materials that can be used without compromising performance of the GLP-1 analogue formulations. The present invention has been made on the basis of these findings.
The pharmaceutical formulations of the present invention surprisingly show less tendency for fibre formation after treating the active ingredient solution at mild heating conditions i.e. lower temperature in comparison to the already known and previously described compositions and conditions for the preparation of GLP-1 analogue formulations.
4.1. Definitions
According to the present invention and unless specified, all amount indications are provided on a weight basis.
Measurement of pH is performed according to the Ph. Eur. test 2.2.3. Potentiometric determination of pH, where determination of pH is made by measuring the potential difference between the reference electrode and the electrode, sensitive to hydrogen ions.
Measurement of osmolality is performed according to the Ph. Eur. test 2.2.35. Osmolality, where osmolality is determined by measurement of depression of freezing point.
Clarity of solution is measured according to the Ph. Eur. test 2.2.1. Clarity and degree of opalescence of liquids, where clarity can be determined by a visual or an instrumental method.
According to a preferred embodiment, the above tests are carried out as specified in the 9th Edition of Ph. Eur.
Measurement of fibrillation tendency of liraglutide in formulations after inducing heat and mechanical stress is performed with BioTek Synergy Mx multi-mode reader by monitoring flurescence of the amyloid dye thioflavin T (ThT). Experiment is performed on 96-well plate enabling fluorescence measurements with a microplate reader. Sample formulations are transferred to the plate in 190 pL portions followed by addition of 10 pL of 100 pM aqueous ThT and a stainless steel ball to each well. Plate is then kept at 37°C and shaken for 30 s every 15 min. Fluorescence of ThT is recorded for minimum 48 hours with excitation wavelength 440 nm and emission wavelength 480 nm. Background is measured on the same plate with placebo solution (water for injection and excipients) treated in the same way as formulation solution. Comparison of fibrillation tendencies of the samples is performed by direct visual comparison of the curves of relative fluorescence units (RFU) as a function of time, or by comparison of the time needed for the signal to reach certain intensity of the fluorescence. Parameter t(15000) defines time from the start of the experiment to the signal reaching 15000 RFU. As more fibrils result in increased RFU, shorter times represent higher fibrillation tendencies.
If no temperature is specified, the temperature for carrying out the described methods is not particularly restricted. Unless the context dictates otherwise, the described operations may for instance be carried out at any temperature within the normal room temperature range, i.e. 15- 30°C, such as 20-25°C and more specifically 21-23°C.
The term “final volume” is meant to characterize the volume that is obtained when adding sufficient water for injections to reach the intended concentration of the GLP-1 peptide, such as, in embodiments of the present invention, the concentrations specified in Section 4.2 below.
4.2. Active pharmaceutical ingredient
In one embodiment, the GLP-1 peptide analogue such as exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide and semaglutide is any peptide that binds to Glucagon-like peptide- 1
receptor, commonly found on beta cells of the pancreas and on neurons of the brain, and acts as an agonist for the receptor.
In one embodiment of the present invention the GLP-1 analogue is liraglutide. Liraglutide was first described in WO99/43705. The term liraglutide as used in the present invention denotes liraglutide and all pharmaceutically acceptable salts, hydrates, solvates, prodrugs, chelates and complexes thereof.
In one embodiment liraglutide prior to freeze drying according to the present invention has a pH ofbetween 7 to 12, preferably between 7.2 to 11.8, more preferably between 7.5 to 11.5.
In one embodiment the concentration of liraglutide present in the pharmaceutical composition according to the present invention is from 0.1 to 100 mg/ml.
In another embodiment the concentration of liraglutide present in the pharmaceutical composition according to the present invention is from 0.5 to 50 mg/ml.
In yet another embodiment the concentration of liraglutide present in the pharmaceutical composition according to the present invention is from 1 to 10 mg/ml.
In one embodiment the concentration of semaglutide present in the pharmaceutical composition according to the present invention is from 0.1 to 100 mg/ml.
In another embodiment the concentration of semaglutide present in the pharmaceutical composition according to the present invention is from 0.5 to 50 mg/ml.
In yet another embodiment the concentration of semaglutide present in the pharmaceutical composition according to the present invention is from 1 to 10 mg/ml.
GLP-1 peptide analogue used in the pharmaceutical composition according to the present invention may be prepared according to any manufacturing process known from the state art such as for example US6268343, US7273921, US6451974, W02000055119,
W02005019261, W02005019262, W02005058954, W02007090496, WO2010029159, WO2013037266, WO2013117135, CN104045705, CN104045706, CN103275208,
CN103275208, WO2014199397, CN103288951, CN103304659, CN103304660,
CN103087181, W02015100876, CN103864918, CN103864918, CN104004083,
W02016005960, WO2016046753, W02016059609, WO2016067271, CN104650219,
CN104745597, W02017007324, CN105017381, CN106478805, CN105732798,
CN105294853, WO2017138855, WO2017162650, CN107286234, W02018020417, WO20 18020417, WO2018032521, CN106397573, WO2018104922, CN106699871, CN107056927, CN107022021.
In one embodiment of the present invention the GLP-1 analogue is semaglutide. Semaglutide was first described in WO 2006/097537. The term semaglutide as used in the present invention denotes semaglutide and all pharmaceutically acceptable salts, hydrates, solvates, prodrugs, chelates and complexes thereof.
In one embodiment the pharmaceutical composition according to the present invention may further comprise any other active ingredients suitable to be incorporated into the same composition, for example active ingredients for treatment of cardiovascular diseases or active ingredients for treatment of diabetes, such as for example insulin, insulin analogues or any other antidiabetic drugs.
4.3. Buffering agent
The pharmaceutical composition of the present invention is designated by the use of at least one buffering agent. The term buffering agent as used in the present invention denotes a compound used to maintain the pH near a desired value. A suitable buffering agent can be any compound known to the person skilled in the art as described e.g. in Remington: The Science and Practice of Pharmacy, 22nd Edition, 2013, to maintain the pH in basic environment, e.g. in one of the pH ranges specified in the pharmaceutical composition section below, and which is suitable for using in pharmaceutical compositions. The buffering agent can include, but it is not limited to, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, sodium acetate, sodium carbonate, citrate, meglumine, glycine, histidine, lysine, arginine, asparagine, glutamic acid, sodium glutamate, tris (hydroxymethyl)-aminomethan, methionine, Hepes, maleic acid, malic acid, lactate or any combinations thereof. Each one of these specific buffering agents and combinations thereof constitutes an alternative embodiment of the invention.
The buffering agent to be used according to one embodiment of the present invention is selected from the group consisting of sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, meglumine, glycine, histidine, lysine, arginine, asparagine, methionine, Hepes, maleic acid or any combinations thereof.
The buffering agent to be used according to one embodiment of the present invention is selected from the group consisting of asparagine, methionine, Hepes, maleic acid or any combinations thereof.
In one embodiment the concentration of buffering agent used in the pharmaceutical composition of the present invention is in the range of 0.05 - 50 mg/ml.
In one embodiment the concentration of buffering agent used in the pharmaceutical composition of the present invention is in the range of 0.1 - 30 mg/ml.
In one embodiment the concentration of buffering agent used in the pharmaceutical composition of the present invention is in the range of 0.1 - 20 mg/ml.
4.4. Tonicity agent
The pharmaceutical composition of the present invention is designated by the use of at least one tonicity agent which is propylene glycol.
In addition to propylene glycol any other pharmaceutically acceptable excipient known to the person skilled in the art as the tonicity agent and as described e.g. in Remington: The Science and Practice of Pharmacy, 22nd Edition, 2013, to provide the effective osmolality i.e. to adjust the osmolality of the solution to that which is almost isotonic to blood plasma, for instance the osmolality ranges indicated in the pharmaceutical composition section below could be used. The additional tonicity agent can include, but it is not limited to xylitol, sorbitol, PEG 400, sucrose, glucose, fructose, lactose, maltose, galactose, sodium chloride, glycerol, mannitol and trehalose or any combinations thereof. Each one of these specific tonicity agents and combinations thereof constitutes an alternative embodiment of the invention. In one further embodiment of the invention, propylene glycol is used as the only tonicity agent.
In one embodiment the concentration of tonicity agent or total concentration of combination of tonicity agents (if multiple tonicity agents are present) used in the pharmaceutical composition of the present invention is in the range of 0.5 - 120 mg/ml.
In one embodiment the concentration of tonicity agent or total concentration of combination of tonicity agents (if multiple tonicity agents are present) used in the pharmaceutical composition of the present invention is in the range of 0.5 - 100 mg/ml.
In one embodiment the concentration of tonicity agent used or total concentration of combination of tonicity agents (if multiple tonicity agents are present) in the pharmaceutical composition of the present invention is in the range of 1 - 80 mg/ml.
4.5. Preservative
The pharmaceutical composition of the present invention is designated by the use of at least one preservative. The term preservative as used in the present invention denotes any pharmaceutically acceptable excipient known to the person skilled in the art as described e.g. in Remington: The Science and Practice of Pharmacy, 22nd Edition, 2013, used to prevent microbial growth. Multidose aqueous preparations provide excellent growth media for microorganisms, such as molds, yeast and bacteria and therefore require the presence of an antimicrobial preservative to maintain aseptic conditions throughout their shelf life. The preservative can include, but it is not limited to phenol, m-cresol, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, benzoic acid, benzyl alcohol, benzyl benzoate, 2-phenoxyethanol, butyl p-hydroxybenzoate, 2-phenylethanol, benzyl alcohol, chlorobutanol, acetone sodium bisulfite, benzalkonium chloride, benzethonium chloride and thiomerosal, or any combinations thereof. Each one of these specific preservatives and combinations thereof constitutes an alternative embodiment of the invention.
The preservative to be used according to one embodiment of the present invention is selected from the group consisting of phenol, m-cresol, methyl p-hydroxybenzoate, propyl p- hydroxybenzoate, 2-phenylethanol, benzyl alcohol, chlorobutanol or any combinations thereof.
The preservative to be used according to one embodiment of the present invention is selected from the group consisting of phenol and benzyl alcohol.
The preservative to be used according to one embodiment of the present invention is phenol.
In one embodiment the concentration of preservative used in the pharmaceutical composition of the present invention is in the range of 0.5 to 30 mg/ml.
In one embodiment the concentration of preservative used in the pharmaceutical composition of the present invention is in the range of 0.5 to 20 mg/ml.
In one embodiment the concentration of preservative used in the pharmaceutical composition of the present invention is in the range of 1 to 10 mg/ml.
4.6. Other pharmaceutically acceptable excipients
The pharmaceutical composition according to the present invention optionally further comprises other pharmaceutically acceptable excipients selected among any known state of the art for pharmaceutical ingredients used in liquid dosage forms, as described e.g. in Remington: The Science and Practice of Pharmacy, 22nd Edition, 2013.
Particularly, other pharmaceutically acceptable excipients present in the pharmaceutical composition according to the present invention can be selected from the group consisting of, but not limited to, one or more solvents, one or more chelating agents, one or more stabilisers, one or more pH adjusting agents, one or more antioxidants, one or more surfactants or any combinations thereof.
As the pH is one of the critical quality attributes of the present invention, pH adjustment is necessary whenever the pH deviates from the target pH: suitable pH adjusting agents include, but are not limited to HC1 and NaOH.
4.7. Pharmaceutical composition
The pharmaceutical composition of the present invention is in the form of a solution.
In one embodiment the pharmaceutical composition according to the present invention is a clear solution with no visible particles.
In one embodiment the pH of the pharmaceutical composition according to the present invention is in the range of 7 to 12.
In one embodiment the pH of the pharmaceutical composition according to the present invention is in the range of 7 to 10.
In one embodiment the pH of the pharmaceutical composition according to the present invention is in the range of 7 to 9.
In one embodiment the pH of the pharmaceutical composition according to the present invention is in the range of 7 to 8.
In one embodiment the pH of the pharmaceutical composition according to the present invention is in the range of 7.9 to 8.4.
In one embodiment the pharmaceutical composition according to the present invention has the osmolality in the range of from 200 to 400 mOsmol/kg.
In one embodiment the pharmaceutical composition according to the present invention has the osmolality in the range of from 230 to 370 mOsmol/kg.
In one embodiment the pharmaceutical composition according to the present invention has the osmolality in the range of from 250 to 350 mOsmol/kg.
4.8. Amount of components
The above-mentioned components may be present in amounts as shown in the following table. Amount indications may be understood as indications of absolute weight, the unit being mass concentration, in the final solution.
Advantageous concentrations of the buffer agent, tonicity agent and preservative during the solution preparation are shown in the table below. Amount indications may be understood as indications of absolute weight, the unit being mass concentration, in solution a) of Methods B and C.
Advantageous concentration of the active substance during the solution preparation is shown in the table below. Amount indications may be understood as indications of absolute weight, the unit being mass concentration, in solution c) of Methods B and C.
4.9. Manufacturing method
The processes of the present invention comprise the following steps as specified in Methods B and C below. Method A is provided for comparison:
Method A a) dissolving the preservative, the buffering agent and the tonicity agent in water for injections (WFI), b) adjusting the pH of solution a),
c) adding the GLP-1 analogue, d) adjusting the pH of solution c), e) adding WFI up to the final volume.
In addition, the processes of the present invention comprise the following steps:
Method B a) dissolving the preservative, the buffering agent and the tonicity agent in water for injections (WFI), b) adjusting the pH of solution a), c) dissolving the GLP-1 analogue in WFI, d) adjusting the pH of solution c), e) heating of the solution d), f) cooling down of the solution e), g) combining solutions b) and f), h) adjusting the pH of solution g), i) adding WFI up to the final volume.
In one embodiment, the process of the present invention comprises the following steps:
Method C a) dissolving the preservative, the buffering agent and the tonicity agent in water for injections (WFI), b) adjusting the pH of solution a), c) dissolving the GLP-1 analogue in WFI by stirring, d) adjusting the pH of solution c), e) heating of the solution d), f) cooling down of the solution e), g) combining solutions b) and f) by stirring, h) adjusting the pH of solution g), i) adding WFI up to the final volume, j) filtration of solution i) and filling into cartridges.
In one embodiment of Methods B and C the temperature of heating in step e) is between 26 and 49°C.
In another embodiment of Methods B and C the temperature of heating in step e) is between
27 and 48°C.
In another embodiment of Methods B and C the temperature of heating in step e) is between
28 and 45°C.
In another embodiment of Methods B and C the temperature of heating in step e) is between
29 and 44°C.
In another embodiment of Methods B and C the temperature of heating in step e) is between
30 and 43°C.
The heating of step e) in some embodiments of Methods B and C is continued for at least 6 hours.
The heating of step e) in some embodiments of Methods B and C is continued for at least 4 hours.
In one embodiment of Methods B and C the heating of step e) is continued for at least 3 hours.
In another embodiment of Methods B and C the heating of step e) is continued for at least 2 hours.
In one embodiment of Methods B and C the heating of step e) lasts between 1-6 hours, preferably between 1.5-5 hours, more preferably between 2-4 hours.
In one embodiment of Methods B and C, the cooling of step f) is down to a temperature of 15- 30°C, preferably 20-25°C. Of course, the cooling down operation requires that the end temperature is selected to be lower than the starting temperature (i.e. the temperature of heating in step e)).
In one embodiment of Methods A, B and C the pH of solution a) in step b) is adjusted to 7-8, preferably 7-7.7.
In one embodiment of Methods B and C the pH of solution c) in step d) is adjusted to 8-11, preferably 9-10.
In one embodiment of Method A the pH of solution c) in step d) is adjusted to around 8-9, preferably 8-8.5, more preferably 8.15.
In one embodiment of Methods B and C the pH of solution g) in step h) is adjusted to around 8-9, preferably 8-8.5, more preferably 8.15.
In one embodiment of Methods B and C the temperature of the solution e) in step f) is 15- 30°C, preferably 20-25°C.
In one embodiment of Method C filtration of solution i) is the sterile filtration.
For each of the methods of the invention, the above process conditions can be combined as desired. Such combinations of process conditions are preferred. Especially preferred are the combination of heating temperatures of 30 to 45°C with heating times of 1-6 hours, 1.5-5 hours or 2-4 hours, the combination of heating temperatures of 32 to 44°C with heating times of 1-6 hours, 1.5-5 hours or 2-4 hours and the combination of heating temperatures of 33 to 43°C with heating times of 1-6 hours, 1.5-5 hours or 2-4 hours. Most preferably are these listed combinations of heating temperatures and heating times when they are applied in the context of making pharmaceutical compositions containing propylene glycol as tonicity agent.
According to a preferred embodiment, a first solution (excipient solution) is prepared by dissolving disodium phosphate dihydrate as buffering agent (0.4 - 80 mg/ml), phenol as preservative (4 - 40 mg/ml) and propylene glycol as tonicity agent (4 - 320 mg/ml) in water for injections (WFI) and adjusting the pH to about 7-7.7. A second solution (liraglutide active ingredient solution) is prepared by dissolving liraglutide in WFI (2 - 20 mg/ml) while stirring. This is followed by adjusting the pH to about 9-10. Then the resulting liraglutide active ingredient solution is heated to 32-38°C and maintained at that temperature for a period of 2
hours to 6 hours. After cooling down the liraglutide active ingredient solution to 20-25°C, it is combined with the excipient solution under stirring. The pH is then adjusted to about 8.0 - 8.3 and the resulting solution is filtered through a sterilizing-grade filter and filled into a container.
The present invention also pertains to the pharmaceutical compositions obtainable by any one of the methods specified herein. Any specific product characteristic obtainable by the specified methods is to be understood as a characteristic of pharmaceutical compositions of certain embodiments of the present invention. These process-derived characteristics may also be present in combination with any one of the further features described elsewhere in the present application.
5. Examples
Preferred specific embodiments of the present invention are described in the following examples. It is, however, to be understood that the present invention is not limited to these examples.
5.1. Example 1
Table 1
Solution 1 (excipient solution) was prepared by dissolving the buffering agent (Hepes or asparagine), phenol as the preservative and the tonicity agent (propylene glycol) in water for injections (WFI) and adjusting the pH to about 7-7.7. Solution 2 was prepared by dissolving liraglutide in WFI by stirring slowly, adjusting the pH to about 9-10, then heating the
liraglutide active ingredient solution at 35°C or 70°C for 1, 2 or 6 hours. After cooling down the liraglutide active ingredient solution to around 20-25°C, it was combined with the excipient solution by stirring slowly and the pH was adjusted to around 8.15. The solution was then filtered through a sterilizing-grade filter and filled into 3 ml cartridges.
5.2. Example 2 Table 2:
The compositions F5 to F9 are prepared by the same process as disclosed in Example 1.
5.3. Example 3 Table 3:
The compositions F10 to F14 are prepared by the same process as disclosed in Example 1.
5.4. Example 4: Fibrillation tendency of formulations with the liraglutide active ingredient solution treated at temperature 35/70°C for lh, 2h and 6h
Solution 1 (excipient solution) was prepared by dissolving the buffering agent (disodium phosphate dihydrate, 4.7 mg/ml), phenol as the preservative (18.3 mg/ml) and the tonicity agent (propylene glycol, 47 mg/ml) in water for injections (WFI) and adjusting the pH to about 7-7.7. Solution 2 was prepared by dissolving liraglutide in WFI (10 mg/ml) by stirring slowly, adjusting the pH to about 9-10, then heating the liraglutide active ingredient solution at 35°C or 70°C for 1 hour, 2 hours or 6 hours. After cooling down the liraglutide active ingredient solution to around 20-25°C, it was combined with the excipient solution by stirring slowly, the pH was adjusted to around 8.15 and the water for injections added up to the final volume. The solution was then filtered through a sterilizing-grade filter and filled into 3 ml cartridges. (Figure 1).
Surprisingly, we have found that the propylene glycol-containing excipient solution exerts a stabilizing effect on the liraglutide structure and slows down the tendency for fibre formation, when the liraglutide active ingredient solution is treated at mild heating conditions (35°C), before combining it with the excipient solution. As is evident from Figure 1 treating the liraglutide active ingredient solution at 35°C for at least 2 hours attenuates the tendency for fibre formation when compared to treating the same solution at 70°C for 1 hour. Surprisingly, treating the liraglutide active ingredient solution at 35°C for 2 hours already achieves the same effect on the fibrillation tendency as treating the solution for 6 hours.
Lower temperature treatment of the liraglutide active ingredient solution is preferable to the treatment at higher temperatures, since stability of peptides in solutions is highly affected by elevated temperatures. The effect of temperature stress on the stability of liraglutide is considerably lower at 35°C, therefore prolonging the temperature treatment at mild temperatures to at least 2 hours is more favourable not only in terms of fibre formation, but also in terms of related substances generation.
Claims
1. A method for the preparation of pharmaceutical composition comprising at least one GLP-1 peptide analogue, propylene glycol, at least one buffering agent, at least one preservative and optionally other pharmaceutically acceptable excipients, which comprises the following steps: a) dissolving the preservative, the buffering agent and propylene glycol in water for injections, b) adjusting the pH of solution a) to a pH of 7-8, c) dissolving the GLP-1 peptide analogue in water for injections, d) adjusting the pH of solution c) to a pH of 8- 11 , e) heating the solution d) to a temperature of 26-49°C, f) cooling down solution e) to a temperature of 15-30°C, preferably 20-25°C, g) combining solutions b) and f), h) adjusting the pH of solution g), i) adding water for injections up to the final volume.
2. The method according to claim 1 wherein the temperature of heating in step e) is between 27-48°C, preferably between 28 to 45°C, more preferably 29-44°C and even more preferably between 30 to 43 °C.
3. The method according to claim 1 or 2 wherein the heating of step e) is continued for at least 2 hours, at least 4 hours and preferably at least 6 hours.
4. The method according to claim 1 or 2 wherein the heating of step e) is continued for 1-6 hours, preferably between 1.5-5 hours, more preferably between 2-4 hours.
5. The method according to any one of claims 1 to 4, wherein the product obtained in the last step is subsequently sterile filtered and then filled into a container, preferably a cartridge.
6. The method according to any one of claims 1 to 5, wherein the GLP-1 peptide analogue is liraglutide.
7. The method according to any one of claims 1 to 5, wherein the GLP-1 peptide analogue is semaglutide.
8. A pharmaceutical composition comprising at least one GLP-1 peptide analogue, propylene glycol, at least one buffering agent, at least one preservative and optionally other pharmaceutically acceptable excipients, which is obtainable by the method according to any one of claims 1 to 7.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114395597A (en) * | 2021-12-17 | 2022-04-26 | 佛山汉腾生物科技有限公司 | Hydroxylation detection method of GLP-1 or variant thereof |
| CN116159027A (en) * | 2022-12-29 | 2023-05-26 | 江苏诺泰澳赛诺生物制药股份有限公司 | Semiglutide freeze-dried pharmaceutical composition and preparation method thereof |
Citations (62)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999043705A1 (en) | 1998-02-27 | 1999-09-02 | Novo Nordisk A/S | N-terminally truncated glp-1 derivatives |
| WO2000055119A1 (en) | 1999-03-17 | 2000-09-21 | Novo Nordisk A/S | Method for acylating peptides and novel acylating agents |
| US6268343B1 (en) | 1996-08-30 | 2001-07-31 | Novo Nordisk A/S | Derivatives of GLP-1 analogs |
| WO2001077141A1 (en) * | 2000-04-06 | 2001-10-18 | Novo Nordisk A/S | Shock heat treatment of polypeptides |
| US6451974B1 (en) | 1999-03-17 | 2002-09-17 | Novo Nordisk A/S | Method of acylating peptides and novel acylating agents |
| WO2003002136A2 (en) | 2001-06-28 | 2003-01-09 | Novo Nordisk A/S | Stable formulation of modified glp-1 |
| WO2004105790A1 (en) | 2003-06-03 | 2004-12-09 | Novo Nordisk A/S | Stabilized pharmaceutical peptide compositions |
| WO2004105781A2 (en) | 2003-06-03 | 2004-12-09 | Novo Nordisk A/S | Stabilized pharmaceutical peptide compositions |
| WO2005019262A1 (en) | 2003-08-21 | 2005-03-03 | Novo Nordisk A/S | Purification of glucagon-like peptides |
| WO2005019261A1 (en) | 2003-08-21 | 2005-03-03 | Novo Nordisk A/S | Separation of polypeptides comprising a racemized amino acid |
| WO2005049061A2 (en) | 2003-11-20 | 2005-06-02 | Novo Nordisk A/S | Propylene glycol-containing peptide formulations which are optimal for production and for use in injection devices |
| WO2005058954A1 (en) | 2003-12-18 | 2005-06-30 | Novo Nordisk A/S | Novel glp-1 compounds |
| WO2006097537A2 (en) | 2005-03-18 | 2006-09-21 | Novo Nordisk A/S | Acylated glp-1 compounds |
| WO2007090496A1 (en) | 2006-02-08 | 2007-08-16 | Lonza Ag | Synthesis of glucagon-like peptide |
| US7273921B2 (en) | 2002-09-25 | 2007-09-25 | Novo Nordisk A/S | Method for producing acylated peptides |
| WO2007146448A1 (en) | 2006-06-07 | 2007-12-21 | Nastech Pharmaceutical Company Inc. | Pharmaceutical formulations of glp-1 derivatives |
| US20080125361A1 (en) * | 2004-11-12 | 2008-05-29 | Novo Nordisk A/S | Stable Formulations Of Peptides |
| WO2010029159A1 (en) | 2008-09-12 | 2010-03-18 | Novo Nordisk A/S | Method of acylating a peptide or protein |
| CN102429876A (en) | 2011-12-14 | 2012-05-02 | 深圳翰宇药业股份有限公司 | Liraglutide sustained-release microsphere preparation and preparation method thereof |
| EP2494983A1 (en) | 2004-11-12 | 2012-09-05 | Novo Nordisk A/S | Stable formulations of GLP-1 |
| WO2013037266A1 (en) | 2011-09-14 | 2013-03-21 | 深圳翰宇药业股份有限公司 | Method for solid phase synthesis of liraglutide |
| CN103087181A (en) | 2013-01-17 | 2013-05-08 | 刘卫 | Solid-phase synthesis method of liraglutide |
| WO2013117135A1 (en) | 2012-02-10 | 2013-08-15 | 深圳翰宇药业股份有限公司 | Method for purifying solid-phase synthetic crude liraglutide |
| CN103275208A (en) | 2013-05-27 | 2013-09-04 | 成都圣诺生物制药有限公司 | Preparation method for liraglutide |
| CN103288951A (en) | 2013-06-19 | 2013-09-11 | 深圳翰宇药业股份有限公司 | Preparation method of liraglutide |
| CN103304659A (en) | 2013-06-19 | 2013-09-18 | 深圳翰宇药业股份有限公司 | Solid-phase preparation method of liraglutide |
| CN103304660A (en) | 2013-07-12 | 2013-09-18 | 上海昂博生物技术有限公司 | Synthetic method of liraglutide |
| CN103864918A (en) | 2014-03-31 | 2014-06-18 | 哈尔滨吉象隆生物技术有限公司 | Solid-phase synthesis method for liraglutide |
| CN104004083A (en) | 2014-06-13 | 2014-08-27 | 成都圣诺生物科技股份有限公司 | Method for synthesizing liraglutide |
| CN104045706A (en) | 2013-03-12 | 2014-09-17 | 深圳翰宇药业股份有限公司 | Synthetic method of liraglutide |
| CN104045705A (en) | 2013-03-12 | 2014-09-17 | 深圳翰宇药业股份有限公司 | Synthetic method of liraglutide |
| WO2014199397A2 (en) | 2013-06-11 | 2014-12-18 | Mylan Laboratories Ltd | Process for the preparation of liraglutide |
| CN104650219A (en) | 2015-02-15 | 2015-05-27 | 兰州大学 | Method for preparing liraglutide by convergent synthesis |
| CN104745597A (en) | 2015-03-27 | 2015-07-01 | 杭州北斗生物技术有限公司 | Method for efficiently expressing recombinant liraglutide |
| WO2015100876A1 (en) | 2014-01-03 | 2015-07-09 | 杭州阿德莱诺泰制药技术有限公司 | Method for preparing liraglutide |
| CN105017381A (en) | 2015-07-20 | 2015-11-04 | 吉尔生化（上海）有限公司 | Purification method of liraglutide |
| WO2016005960A1 (en) | 2014-07-11 | 2016-01-14 | Dr. Reddy's Laboratories Limited | Process for preparation of liraglutide |
| CN105294853A (en) | 2015-11-13 | 2016-02-03 | 中肽生化有限公司 | Preparation method for liraglutide |
| WO2016038521A1 (en) | 2014-09-08 | 2016-03-17 | Sun Pharmaceutical Industries Limited | Pharmaceutical compositions of liraglutide |
| WO2016046753A1 (en) | 2014-09-23 | 2016-03-31 | Novetide, Ltd. | Synthesis of glp-1 peptides |
| WO2016059609A1 (en) | 2014-10-17 | 2016-04-21 | Dr. Reddy' S Laboratories Limited | Acylation process for preparation of liraglutide |
| WO2016067271A1 (en) | 2014-10-31 | 2016-05-06 | Auro Peptides Ltd | A process for the preparation of liraglutide |
| CN105732798A (en) | 2015-11-03 | 2016-07-06 | 江苏诺泰生物制药股份有限公司 | Synthetic method for liraglutide |
| WO2017007324A1 (en) | 2015-07-09 | 2017-01-12 | Enzypep B.V. | Designing an enzymatic peptide fragment condensation strategy |
| CN106397573A (en) | 2016-10-24 | 2017-02-15 | 合肥国肽生物科技有限公司 | Solid-phase synthesis method of liraglutide |
| CN106478805A (en) | 2015-08-28 | 2017-03-08 | 甘李药业股份有限公司 | A kind of preparation method of GLP-1 derivant |
| CN106699871A (en) | 2016-12-27 | 2017-05-24 | 哈药集团技术中心 | Preparation method of liraglutide |
| CN107022021A (en) | 2017-03-24 | 2017-08-08 | 吉尔生化（上海）有限公司 | A kind of solid-phase synthesis of Liraglutide |
| WO2017138855A1 (en) | 2016-02-11 | 2017-08-17 | Polypeptide Laboratories Holding (Ppl) Ab | Method for preparation of liraglutide using bal linker |
| CN107056927A (en) | 2017-01-16 | 2017-08-18 | 四川吉晟生物医药有限公司 | A kind of preparation method of Liraglutide |
| WO2017147783A1 (en) | 2016-03-01 | 2017-09-08 | 深圳翰宇药业股份有限公司 | Pharmaceutical composition and manufacturing method thereof |
| WO2017162650A1 (en) | 2016-03-23 | 2017-09-28 | Bachem Holding Ag | Method for preparing glucagon-like peptides |
| CN107286234A (en) | 2016-03-31 | 2017-10-24 | 深圳翰宇药业股份有限公司 | A kind of method for reducing and/or removing default peptide in Solid-phase synthesis peptides |
| WO2018020417A1 (en) | 2016-07-27 | 2018-02-01 | Dr. Reddy's Laboratories Limited | Process for preparation of protein or peptide |
| WO2018032521A1 (en) | 2016-08-19 | 2018-02-22 | 深圳市健元医药科技有限公司 | Method for synthesizing liraglutide |
| WO2018096460A1 (en) | 2016-11-22 | 2018-05-31 | Biocon Research Limited | Pharmaceutical compositions of glp-1 analogues |
| WO2018104922A1 (en) | 2016-12-10 | 2018-06-14 | Biocon Limited | Synthesis of liraglutide |
| WO2019038412A1 (en) * | 2017-08-24 | 2019-02-28 | Novo Nordisk A/S | Glp-1 compositions and uses thereof |
| WO2019110837A1 (en) | 2017-12-07 | 2019-06-13 | Adocia | Compositions in the form of an injectable aqueous solution comprising human glucagon and a copolyamino acid |
| WO2019193204A1 (en) | 2018-04-06 | 2019-10-10 | Cyprumed Gmbh | Pharmaceutical compositions for the transmucosal delivery of therapeutic peptides and proteins |
| CN110339166A (en) | 2018-04-04 | 2019-10-18 | 沈阳药科大学 | A kind of Liraglutide multivesicular liposome and its preparation method and application |
| CN110368376A (en) | 2019-08-08 | 2019-10-25 | 浙江美华鼎昌医药科技有限公司 | A kind of Liraglutide sustained-release microspherical composition and preparation method thereof |
-
2020
- 2020-12-18 WO PCT/EP2020/087105 patent/WO2021123228A1/en active Application Filing
Patent Citations (63)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6268343B1 (en) | 1996-08-30 | 2001-07-31 | Novo Nordisk A/S | Derivatives of GLP-1 analogs |
| WO1999043705A1 (en) | 1998-02-27 | 1999-09-02 | Novo Nordisk A/S | N-terminally truncated glp-1 derivatives |
| US6451974B1 (en) | 1999-03-17 | 2002-09-17 | Novo Nordisk A/S | Method of acylating peptides and novel acylating agents |
| WO2000055119A1 (en) | 1999-03-17 | 2000-09-21 | Novo Nordisk A/S | Method for acylating peptides and novel acylating agents |
| WO2001077141A1 (en) * | 2000-04-06 | 2001-10-18 | Novo Nordisk A/S | Shock heat treatment of polypeptides |
| WO2003002136A2 (en) | 2001-06-28 | 2003-01-09 | Novo Nordisk A/S | Stable formulation of modified glp-1 |
| US7273921B2 (en) | 2002-09-25 | 2007-09-25 | Novo Nordisk A/S | Method for producing acylated peptides |
| WO2004105790A1 (en) | 2003-06-03 | 2004-12-09 | Novo Nordisk A/S | Stabilized pharmaceutical peptide compositions |
| WO2004105781A2 (en) | 2003-06-03 | 2004-12-09 | Novo Nordisk A/S | Stabilized pharmaceutical peptide compositions |
| WO2005019262A1 (en) | 2003-08-21 | 2005-03-03 | Novo Nordisk A/S | Purification of glucagon-like peptides |
| WO2005019261A1 (en) | 2003-08-21 | 2005-03-03 | Novo Nordisk A/S | Separation of polypeptides comprising a racemized amino acid |
| WO2005049061A2 (en) | 2003-11-20 | 2005-06-02 | Novo Nordisk A/S | Propylene glycol-containing peptide formulations which are optimal for production and for use in injection devices |
| WO2005058954A1 (en) | 2003-12-18 | 2005-06-30 | Novo Nordisk A/S | Novel glp-1 compounds |
| EP2494983B1 (en) | 2004-11-12 | 2019-04-24 | Novo Nordisk A/S | Stable formulations of glp-1 |
| US20080125361A1 (en) * | 2004-11-12 | 2008-05-29 | Novo Nordisk A/S | Stable Formulations Of Peptides |
| EP2494983A1 (en) | 2004-11-12 | 2012-09-05 | Novo Nordisk A/S | Stable formulations of GLP-1 |
| WO2006097537A2 (en) | 2005-03-18 | 2006-09-21 | Novo Nordisk A/S | Acylated glp-1 compounds |
| WO2007090496A1 (en) | 2006-02-08 | 2007-08-16 | Lonza Ag | Synthesis of glucagon-like peptide |
| WO2007146448A1 (en) | 2006-06-07 | 2007-12-21 | Nastech Pharmaceutical Company Inc. | Pharmaceutical formulations of glp-1 derivatives |
| WO2010029159A1 (en) | 2008-09-12 | 2010-03-18 | Novo Nordisk A/S | Method of acylating a peptide or protein |
| WO2013037266A1 (en) | 2011-09-14 | 2013-03-21 | 深圳翰宇药业股份有限公司 | Method for solid phase synthesis of liraglutide |
| CN102429876A (en) | 2011-12-14 | 2012-05-02 | 深圳翰宇药业股份有限公司 | Liraglutide sustained-release microsphere preparation and preparation method thereof |
| WO2013117135A1 (en) | 2012-02-10 | 2013-08-15 | 深圳翰宇药业股份有限公司 | Method for purifying solid-phase synthetic crude liraglutide |
| CN103087181A (en) | 2013-01-17 | 2013-05-08 | 刘卫 | Solid-phase synthesis method of liraglutide |
| CN104045705A (en) | 2013-03-12 | 2014-09-17 | 深圳翰宇药业股份有限公司 | Synthetic method of liraglutide |
| CN104045706A (en) | 2013-03-12 | 2014-09-17 | 深圳翰宇药业股份有限公司 | Synthetic method of liraglutide |
| CN103275208A (en) | 2013-05-27 | 2013-09-04 | 成都圣诺生物制药有限公司 | Preparation method for liraglutide |
| WO2014199397A2 (en) | 2013-06-11 | 2014-12-18 | Mylan Laboratories Ltd | Process for the preparation of liraglutide |
| CN103304659A (en) | 2013-06-19 | 2013-09-18 | 深圳翰宇药业股份有限公司 | Solid-phase preparation method of liraglutide |
| CN103288951A (en) | 2013-06-19 | 2013-09-11 | 深圳翰宇药业股份有限公司 | Preparation method of liraglutide |
| CN103304660A (en) | 2013-07-12 | 2013-09-18 | 上海昂博生物技术有限公司 | Synthetic method of liraglutide |
| WO2015100876A1 (en) | 2014-01-03 | 2015-07-09 | 杭州阿德莱诺泰制药技术有限公司 | Method for preparing liraglutide |
| CN103864918A (en) | 2014-03-31 | 2014-06-18 | 哈尔滨吉象隆生物技术有限公司 | Solid-phase synthesis method for liraglutide |
| CN104004083A (en) | 2014-06-13 | 2014-08-27 | 成都圣诺生物科技股份有限公司 | Method for synthesizing liraglutide |
| WO2016005960A1 (en) | 2014-07-11 | 2016-01-14 | Dr. Reddy's Laboratories Limited | Process for preparation of liraglutide |
| WO2016038521A1 (en) | 2014-09-08 | 2016-03-17 | Sun Pharmaceutical Industries Limited | Pharmaceutical compositions of liraglutide |
| WO2016046753A1 (en) | 2014-09-23 | 2016-03-31 | Novetide, Ltd. | Synthesis of glp-1 peptides |
| WO2016059609A1 (en) | 2014-10-17 | 2016-04-21 | Dr. Reddy' S Laboratories Limited | Acylation process for preparation of liraglutide |
| WO2016067271A1 (en) | 2014-10-31 | 2016-05-06 | Auro Peptides Ltd | A process for the preparation of liraglutide |
| CN104650219A (en) | 2015-02-15 | 2015-05-27 | 兰州大学 | Method for preparing liraglutide by convergent synthesis |
| CN104745597A (en) | 2015-03-27 | 2015-07-01 | 杭州北斗生物技术有限公司 | Method for efficiently expressing recombinant liraglutide |
| WO2017007324A1 (en) | 2015-07-09 | 2017-01-12 | Enzypep B.V. | Designing an enzymatic peptide fragment condensation strategy |
| CN105017381A (en) | 2015-07-20 | 2015-11-04 | 吉尔生化（上海）有限公司 | Purification method of liraglutide |
| CN106478805A (en) | 2015-08-28 | 2017-03-08 | 甘李药业股份有限公司 | A kind of preparation method of GLP-1 derivant |
| CN105732798A (en) | 2015-11-03 | 2016-07-06 | 江苏诺泰生物制药股份有限公司 | Synthetic method for liraglutide |
| CN105294853A (en) | 2015-11-13 | 2016-02-03 | 中肽生化有限公司 | Preparation method for liraglutide |
| WO2017138855A1 (en) | 2016-02-11 | 2017-08-17 | Polypeptide Laboratories Holding (Ppl) Ab | Method for preparation of liraglutide using bal linker |
| WO2017147783A1 (en) | 2016-03-01 | 2017-09-08 | 深圳翰宇药业股份有限公司 | Pharmaceutical composition and manufacturing method thereof |
| WO2017162650A1 (en) | 2016-03-23 | 2017-09-28 | Bachem Holding Ag | Method for preparing glucagon-like peptides |
| CN107286234A (en) | 2016-03-31 | 2017-10-24 | 深圳翰宇药业股份有限公司 | A kind of method for reducing and/or removing default peptide in Solid-phase synthesis peptides |
| WO2018020417A1 (en) | 2016-07-27 | 2018-02-01 | Dr. Reddy's Laboratories Limited | Process for preparation of protein or peptide |
| WO2018032521A1 (en) | 2016-08-19 | 2018-02-22 | 深圳市健元医药科技有限公司 | Method for synthesizing liraglutide |
| CN106397573A (en) | 2016-10-24 | 2017-02-15 | 合肥国肽生物科技有限公司 | Solid-phase synthesis method of liraglutide |
| WO2018096460A1 (en) | 2016-11-22 | 2018-05-31 | Biocon Research Limited | Pharmaceutical compositions of glp-1 analogues |
| WO2018104922A1 (en) | 2016-12-10 | 2018-06-14 | Biocon Limited | Synthesis of liraglutide |
| CN106699871A (en) | 2016-12-27 | 2017-05-24 | 哈药集团技术中心 | Preparation method of liraglutide |
| CN107056927A (en) | 2017-01-16 | 2017-08-18 | 四川吉晟生物医药有限公司 | A kind of preparation method of Liraglutide |
| CN107022021A (en) | 2017-03-24 | 2017-08-08 | 吉尔生化（上海）有限公司 | A kind of solid-phase synthesis of Liraglutide |
| WO2019038412A1 (en) * | 2017-08-24 | 2019-02-28 | Novo Nordisk A/S | Glp-1 compositions and uses thereof |
| WO2019110837A1 (en) | 2017-12-07 | 2019-06-13 | Adocia | Compositions in the form of an injectable aqueous solution comprising human glucagon and a copolyamino acid |
| CN110339166A (en) | 2018-04-04 | 2019-10-18 | 沈阳药科大学 | A kind of Liraglutide multivesicular liposome and its preparation method and application |
| WO2019193204A1 (en) | 2018-04-06 | 2019-10-10 | Cyprumed Gmbh | Pharmaceutical compositions for the transmucosal delivery of therapeutic peptides and proteins |
| CN110368376A (en) | 2019-08-08 | 2019-10-25 | 浙江美华鼎昌医药科技有限公司 | A kind of Liraglutide sustained-release microspherical composition and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| "Remington: The Science and Practice of Pharmacy", 2013 |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114395597A (en) * | 2021-12-17 | 2022-04-26 | 佛山汉腾生物科技有限公司 | Hydroxylation detection method of GLP-1 or variant thereof |
| CN114395597B (en) * | 2021-12-17 | 2024-04-09 | 佛山汉腾生物科技有限公司 | Method for detecting hydroxylation of GLP-1 or variant thereof |
| CN116159027A (en) * | 2022-12-29 | 2023-05-26 | 江苏诺泰澳赛诺生物制药股份有限公司 | Semiglutide freeze-dried pharmaceutical composition and preparation method thereof |
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