Self assembled gels for controlled delivery of encapsulated agents to cartilage

• US 10,568,840 B2
• Filed: 05/08/2017
• Issued: 02/25/2020
• Est. Priority Date: 05/06/2016
• Status: Active Grant

• Current Assignee: Brigham and Women's Hospital Incorporated
• Original Assignee: Brigham and Women's Hospital Incorporated
• Inventors: Karp, Jeffrey, Joshi, Nitin, He, Xueyin, Bhagchandani, Sachin
• Primary Examiner(s): Klinkel, Kortney L.
• Application Number:
  US15/589,891
• Publication Number:
  US 20170319499A1
• Time in Patent Office: 1,023 Days
• CPC Class Codes: A61K 31/10 Sulfides; Sulfoxides; Sulfones
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/245 Amino benzoic acid types, e.g. procaine, novocaine salicylic acid esters A61K31/60
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/7024 Esters of saccharides
• CPC Class Codes: A61K 31/7028 Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: 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
• CPC Class Codes: A61K 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• CPC Class Codes: A61K 9/4833 Encapsulating processes; Filling of capsules mechanical aspects A61J3/07
• CPC Class Codes: A61K 9/5015 Organic compounds, e.g. fats, sugars
• CPC Class Codes: A61K 9/70 Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug hollow drug-filled fibres A61K9/0092
• CPC Class Codes: A61M 31/002 Devices for releasing a drug at a continuous and controlled rate for a prolonged period of time artificial gland structures or devices A61F2/022; intra-uterine contraceptive devices A61F6/14; tampons for introducing into the vagina A61F13/20, A61L15/00; suppositories or bougies for intra-vaginal or intra-uterine application A61K9/02; physical forms of medicinal preparations for sustained or differential drug release A61K9/20, A61K9/50
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease

Abstract

A self-assembled gel composition with enhanced adhesion to cartilage tissue is provided. A cationic agent co-self assembles with a generally regarded as safe (GRAS), low molecular weight (<2,500 Da) gelator, forming homogeneous self-supporting gel that can encapsulate one or more therapeutic agents for controlled release. The composition adheres to connective tissue, e.g., cartilage, to a greater extent and a greater length of time than a self-assembled gel from gelators alone. The composition is used to specifically target connective tissue and deliver one or more therapeutic, prophylactic, or diagnostic agents for controlled release to improve dosing efficacy.

Claims

1. A gel composition which can adhere to cartilage tissue, the gel composition comprising an amphiphilic gelator having a molecular weight of less than 2,500 Da and a cationic agent,

wherein the gelator is an enzyme-cleavable, generally recognized as safe (GRAS) compound selected from the group consisting of ascorbyl alkanoate, sorbitan alkanoate, triglycerol monoalkanoate, sucrose alkanoate, glycocholic acid, retinyl acetate, and alpha-tocopherol acetate, and combinations thereof,

wherein the cationic agent is selected from the group consisting of cationic polysaccharides, 1,2-dioleoyl-3-trimethylammonium propane (DOTAP), 1,2-dioleyloxy-3-trimethylammonium propane chloride (DOTMA), polylysine, and combinations thereof,

wherein the cationic agent is present in an amount greater than 5% by dry weight in a combined mass of the amphiphilic gelator having a molecular weight of less than 2,500 Da and the cationic agent or wherein the cationic agent is present in an amount of at least 0.08 mg/mL of the gel composition,

wherein the gelator and the cationic agent co-self assemble or associate to form a homogeneous gel after heating to dissolution and cooling to room temperature, wherein the homogeneous gel is stable to inversion at a temperature between room and body temperature, and

wherein the cationic agent electrostatically interacts or associates with one or more components of cartilage to enhance adhesion of the homogeneous gel to the cartilage, compared to a control gel composition lacking the cationic agent.

2. The gel composition of claim 1, wherein the cationic agent is present in an amount greater than 10% by dry weight in a combined mass of the amphiphilic gelator having a molecular weight of less than 2,500 Da and the cationic agent.

3. The gel composition of claim 1, wherein the gelator, the cationic agent, or both are compounds meeting the requirements of the U.S. Food and Drug Administration as generally recognized as safe (GRAS) compounds.

4. The gel composition of claim 1, wherein the gelator is an enzyme-cleavable, generally recognized as safe (GRAS) compound selected from the group consisting of ascorbyl alkanoate, sorbitan alkanoate, triglycerol monoalkanoate, sucrose alkanoate, glycocholic acid, and combinations thereof.

5. The gel composition of claim 4, wherein the gelator is selected from the group consisting of ascorbyl palmitate, triglycerol monostearate, sucrose palmitate, and sucrose stearate.

6. The gel composition of claim 1 further comprising one or more therapeutic, prophylactic, or diagnostic agents.

7. The gel composition of claim 6, wherein the one or more therapeutic, prophylactic, or diagnostic agents are released at less than. 10, 15, 20, 25, or 30% from the homogeneous gel when incubated in phosphate buffered saline at 37°

C. for seven days.

8. The gel composition of claim 7, wherein the one or more therapeutic, prophylactic, or diagnostic agents are selected from the group consisting of immunomodulatory agents, chemotherapeutics, analgesics, anesthetics, joint lubricants, anti-pyretic agents, anti-infectious agents, tissue and/or bone regeneration promoters, vitamin, antioxidants, protease inhibitors and small interfering RNA.

9. The gel composition of claim 8 comprising immunomodulatory agents selected from the group consisting of steroids and non-steroidal anti-inflammatories.

10. The gel composition of claim 8 wherein the agent is selected from the group consisting of bone morphogenetic protein, transforming growth factor beta, fibroblast growth factor, stromal cell-derived factor 1 (SDF1), matrix metalloproteinase (MMP) inhibitor, Cathepsin-K inhibitor, and cysteine proteinase inhibitor, and platelet rich plasma.

11. The gel composition of claim 10 comprising Cathepsin-K inhibitors selected from the group consisting of balicatib (AAE581), relacatib (SB-462795), odanacatibe (MK-0822), MV061194, MV061748, MV061940, MV061645, MSX-081, LL-006235, and bicyclic ketone.

12. The gel composition of claim 10 comprising MMP inhibitors selected from the group consisting of CL-82198, actinonin, PD166793, CP 471474, WAY 170523, and ageladine A.

13. The gel composition of claim 10 comprising pain relief agents selected from the group consisting of lidocaine, procaine, tetracaine, dibucaine, and salts thereof.

14. The gel composition of claim 6, wherein the gel composition is free of solvent or the one or more therapeutic, prophylactic, or diagnostic agents which are unencapsulated within the homogeneous gel are removed.

15. The gel composition of claim 1 comprising two or more agents, wherein at least one agent potentiates efficacy of the one or more remaining agents.

16. A dosage unit kit, wherein the dosage unit comprises one or more containers for dry components comprising the amphiphilic gelator and the cationic agent and one or more containers for liquid components comprising one or more solvents, wherein the one or more containers for the dry and liquid components when mixed together form the self-assembled gel composition of claim 1.

17. A composition comprising the gel of claim 1 dispersed or broken up particles that are injectable through a needle when suspended in a carrier.

18. The gel composition of claim 1 wherein solvent is removed by lyophilization, drying or centrifugation.

19. The gel composition of claim 1, wherein the gel composition has an elastic modulus of from 10 to 10,000 Pascal and a viscous modulus of from 10 to 10,000 Pascal.

20. The gel composition of claim 1, wherein the cationic agent is present in an amount greater than 5% by dry weight in a combined mass of the amphiphilic gelator having a molecular weight of less than 2,500 Da and the cationic agent.

21. The gel composition of claim 1, wherein the cationic agent is present in an amount of at least 0.08 mg/mL of the gel composition.

22. A method of preparing a self-assembled gel composition adherent to cartilage tissue, comprising:

combining one or more low molecular weight amphiphilic gelators of less than 2.500 Da, one or more cationic agents, and optionally a therapeutic, prophylactic, or diagnostic agent, to form an organo or hydrogel,

wherein the cationic agent is greater than 10% by weight in a combined mass of the amphiphilic gelator having a molecular weight of less than 2,500 Da and the cationic agent, or is at least 0.08 mg/mL of the self-assembled gel composition.

23. The method of claim 22 wherein the gel composition is homogenized or sonicated to break up the gel into particles which retain the fibrous nanostructures formed in the gel.