# US 11,433,120 B2 · Controlled release peptide formulations

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- Number: US 11,433,120 B2
- Document ID: US11433120B2
- Status: Granted
- Kind: B2
- Application number: 14/117,994
- Filed: 2012-05-25
- Published: 2014-06-12
- Granted: 2022-09-06
- Earliest claimed: 2011-05-25
- Assignees: Camurus AB
- Applicants: Fredrik Tiberg; Catalin Nistor; Markus Johnsson
- Inventors: Fredrik Tiberg; Catalin Nistor; Markus Johnsson
- Web page: https://patentgrep.com/patent/US11433120B2

## CPC

- A61K 38/31: Somatostatins
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/0024: {Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue (compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L)}
- A61K 9/1274: Non-vesicle bilayer structures, e.g. liquid crystals, tubules, cubic phases or cochleates; Sponge phases
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61K 47/14: Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
- A61K 47/24: containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/12: Antidiarrhoeals
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 5/00: Drugs for disorders of the endocrine system
- A61P 5/02: of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
- A61P 5/14: of the thyroid hormones, e.g. T3, T4
- A61P 5/46: for decreasing, blocking or antagonising the activity of glucocorticosteroids
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 27/02: Ophthalmic agents
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 14/655: Somatostatins
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

The present invention relates to compositions forming a low viscosity mixture of: a) 20-80 wt. % of at least one diacyl glycerol and/or a tocopherol; b) 20-80 wt. % of at least one phosphatidyl choline (PC); c) 5-20 wt. % of at least one biocompatible, organic mono-alcoholic solvent; d) up to 20 wt. % polar solvent e) at least one peptide active agent; f) optionally at least one antioxidant; wherein the ratio of components a:b is in the range 40:60 to 54:46; wherein the pre-formulation forms, or is capable of forming, at least one liquid crystalline phase structure upon contact with excess aqueous fluid. The invention further relates to methods of treatment comprising administration of such compositions, and to pre-filled administration devices and kits containing the formulations.

## Claims

### Claim 1

A pre-formulation consisting of a low viscosity mixture of:
a) a lipid component consisting of:
at least 95 wt % of:
a1) 20-80 wt % of at least one diacyl glycerol and/or a tocopherol; and
a2) 20-80 wt % of at least one phosphatidyl choline (PC); and
0-5 wt % of at least one impurity associated with components a1) and/or a2);
b) 5-15 wt % of ethanol;
c) 5-15 wt % of propylene glycol;
d) about 2-5 wt % of octreotide or a halide thereof or a physiologically acceptable acid thereof; and
e) optionally 0.0008-0.1 wt % at least one antioxidant selected from the group consisting of ascorbic acid, EDTA, and citric acid;
wherein the pre-formulation has a viscosity of 10-750 mPas at 20° C.;
wherein the ratio of components a1:a2 is in the range 45:55 to 54:46;
wherein components b) and c) are present in the pre-formulation in an approximately equal amount;
wherein the pre-formulation forms, or is capable of forming, at least one liquid crystalline phase structure upon contact with excess aqueous fluid; and
wherein the pre-formulation is for subcutaneous injection.

### Claim 2 (depends on 1)

The pre-formulation as claimed in claim 1 wherein component a1) comprises glycerol dioleate (GDO).

### Claim 3 (depends on 1)

The pre-formulation as claimed in claim 1 wherein component a2) comprises soy PC.

### Claim 4 (depends on 1)

The pre-formulation as claimed in claim 1 wherein the antioxidant is E DTA.

### Claim 5 (depends on 1)

The pre-formulation as claimed in claim 1 wherein component a1) is present at a level of 30-40% by weight.

### Claim 6 (depends on 1)

The pre-formulation as claimed in claim 1 wherein component a2) is present at a level of 30-40% by weight.

### Claim 7 (depends on 1)

The pre-formulation as claimed in claim 1 wherein component b) is present at a level of 6-14 wt %.

### Claim 8 (depends on 1)

The pre-formulation as claimed in claim 1 wherein the ratio of components a1:a2 is in the range 47:53 to 53:47.

### Claim 9 (depends on 1)

The pre-formulation as claimed in claim 1 wherein the ratio of components c:e is in the range 1:50 to 1:1500.

### Claim 10 (depends on 1)

The pre-formulation as claimed in claim 1 wherein said pre-formulation has an L2 phase structure.

### Claim 11 (depends on 1)

The pre-formulation as claimed in claim 1 comprising at least one formulation from the Table below:
Formulation
Ingredient
OCT(CI)
SPC
GDO
EtOH
PG
A
(wt %)
2.4
43.8
43.8
5.0
5.0
B
(wt %)
2.4
42.3
42.3
6.5
6.5

### Claim 12 (depends on 1)

The pre-formulation as claimed in claim 1 wherein upon administration of said pre-formulation to a human subject, the value Cmax/Cave of said peptide active agent is reduced by a factor of at least 1.2 relative to administration of a corresponding pre-formulation in which component d) is absent.

### Claim 13 (depends on 1)

The pre-formulation as claimed in claim 1 wherein component c) is present at a level of 6-12 wt %.

### Claim 14 (depends on 1)

The pre-formulation as claimed in claim 1 wherein component d) is octreotide, octreotide chloride, or octreotide acetate.

### Claim 15 (depends on 1)

The pre-formulation as claimed in claim 1 wherein component d) is present at a level of about 2-4 wt %.

### Claim 16 (depends on 1)

The pre-formulation as claimed in claim 1 wherein component e) is present.

### Claim 17 (depends on 1)

The pre-formulation as claimed in claim 1 wherein component c) consists of propylene glycol, component d) is octreotide, octreotide chloride, or octreotide acetate, and component e) is present.

### Claim 18 (depends on 17)

The pre-formulation as claimed in claim 17 wherein component d) is present at a level of about 2-4 wt %.

### Claim 19 (depends on 1)

The pre-formulation as claimed in claim 1 wherein the lipid component a) consists of at least 99 wt % of components a1) and a2), and 0-1 wt % of at least one impurity associated with components a1) and/or a2).

### Claim 20 (depends on 1)

The pre-formulation as claimed in claim 1 wherein component b) is present at a level of 8±2 wt %.

### Claim 21 (depends on 1)

The pre-formulation as claimed in claim 1 wherein the ratio of components a1:a2 is in the range of about 50:50.

### Claim 22 (depends on 1)

The pre-formulation as claimed in claim 1 wherein component d) is present at a level of about 3-5 wt %.

### Claim 23 (depends on 1)

The pre-formulation as claimed in claim 1 wherein component d) is present at a level of about 2-3 wt %.

### Claim 24 (depends on 1)

The pre-formulation as claimed in claim 1 wherein component d) is present at a level of about 2-2.5 wt %.

### Claim 25 (depends on 1)

A pre-filled administration device containing the pre-formulation as claimed in claim 1.

### Claim 26 (depends on 25)

The device according to claim 25 wherein said pre-formulation delivers a dosage in the range of 1 to 10 mg/week.

### Claim 27 (depends on 25)

A kit comprising the administration device as claimed in claim 25.

### Claim 28

A process for the formation of a pre-formulation suitable for the administration of a peptide bioactive agent to a subject, said process comprising forming a low viscosity mixture consisting of:
a) a lipid component consisting of:
at least 95 wt % of:
a1) 20-80 wt % of at least one diacyl glycerol and/or a tocopherol; and
a2) 20-80 wt % of at least one phosphatidyl choline (PC); and
0-5 wt % of at least one impurity associated with components a1) and/or a2);
b) 5-15 wt % of ethanol;
c) 5-15 wt % of propylene glycol;
d) about 2-5 wt % of octreotide or a halide thereof or a physiologically acceptable acid thereof; and
e) optionally 0.0008-0.1 wt % at least one antioxidant selected from the group consisting of ascorbic acid, EDTA, and citric acid;
wherein the ratio of components a1:a2 is in the range 45:55 to 54:46;
wherein components b) and c) are present in the pre-formulation in an approximately equal amount;
wherein component d) is dissolved or dispersed in the low viscosity mixture, or in at least one of components a1), a2), b), c) and optionally e) prior to forming the low viscosity mixture;
wherein the pre-formulation formed has a viscosity of 10-750 mPas at 20° C.