Pharmaceutical oil-in-water nano-emulsion

• US 10,736,842 B2
• Filed: 06/25/2015
• Issued: 08/11/2020
• Est. Priority Date: 06/25/2014
• Status: Active Grant

• Current Assignee: Synergia Life Sciences Pvt., Ltd.
• Original Assignee: Synergia Life Sciences Pvt., Ltd.
• Inventors: Misra, Ambikanandan
• Primary Examiner(s): Haghighatian, Mina
• Application Number:
  US15/309,716
• Publication Number:
  US 20170143627A1
• Time in Patent Office: 1,874 Days
• 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 31/4178 not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• 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 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 47/44 Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin synthetic glycerides, e.g. medium-chain triglycerides, A61K47/14
• CPC Class Codes: A61K 9/0043 Nose
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 29/02 : without antiinflammatory effect

Abstract

Accordingly, the present invention provides a pharmaceutical oil-in-water nano-emulsion, with a pharmaceutically active substance. The selected pharmaceutically active substance is encased in monounsaturated fatty acid droplets with the droplets having an average particle size in the range of 60 to 200 nm. The nano-emulsion is also provided with a non-ionic surfactant system, which is a mixture of polyethers, macrogolglycerides and polysaccharides, along with pharmaceutically acceptable adjuvants. The present invention also provides a process for the preparation of pharmaceutical oil-in-water nano-emulsion.

Claims

1. A pharmaceutical oil-in-water nano-emulsion composition, comprising:

a pharmaceutically active substance, encased in monounsaturated fatty acid droplets, wherein said monounsaturated fatty acid is present in an amount of about 5-25% w/w based on the weight of the total composition

said droplets having an average particle size in the range of 60 to 200 nm;

a non-ionic surfactant system comprising a mixture of polyethers, macrogolglycerides and polysaccharides

wherein the polyethers are present in an amount ranging from about 2-25% w/w based on the total weight of the composition,

wherein the macrogolglycerides are present in an amount ranging from 10-30% w/w based on the total weight of the composition,

wherein the polysaccharides are present in an amount ranging from 2-30% w/w based on the total weight of the composition;

water present in an amount of between 15 and 50% w/w; and

pharmaceutically acceptable adjuvants,

wherein the composition is highly stable having a drug loading capacity of the pharmaceutically active substance of up to 100 mg/mL.

2. The composition as claimed in claim 1, wherein said pharmaceutically active substance is lipophilic or partially lipophilic and is selected from a group consisting of antipsychotics, antiemetics, analgesics, antipyretics, anti-inflammatory agents or any lipophilic-based drugs.

3. The composition as claimed in claim 2, wherein said antipsychotics are selected from the group consisting of ziprasidone, fluphenazine, haloperidol, olanzapine, chlorpromazine, risperidone, aripiprazole, molindone, loxapine, and sulpiride and pharmaceutically acceptable salts thereof.

4. The composition as claimed in claim 2, wherein said antiemetics are diphenhydrinate, diphenhydramine, doxylamine, meclizine, ondansetron, promethazine, prochlorperazine, or pharmaceutically acceptable salts thereof.

5. The composition as claimed in claim 2, wherein said analgesics, antipyretics, and anti-inflammatory agents are selected from the group consisting of paracetamol, methadone, diamorphine, fentanyl, buprenorphine, temazepam, piracetam, sufentanil, mefenamic acid, naproxen, piroxicam, indomethacin, valdecoxib, celecoxib, probenecid, nabumetone, ibuprofen, flurbiprofen, isoxicam, meclofenamic acid, fenclozic acid, and phenyl butazone.

6. The composition as claimed in claim 1, wherein said monounsaturated fatty acid is an oleic acid.

7. The composition as claimed in claim 1, wherein said polyether surfactant is a combination of polyethylene glycol and diethylene glycol monoethyl ether.

8. The composition as claimed in claim 1, wherein said polyether surfactant is polyethylene glycol and is present in an amount ranging from about 2.5% to 20% w/w based on the total weight of the composition.

9. The composition as claimed in claim 1, wherein said macrogolglyceride surfactant is caprylocaproyl macrogol-8 glyceride, acconon CC 6, or a combination thereof.

10. The composition as claimed in claim 1, wherein said polysaccharide surfactant is polyoxyethylene sorbitan fatty acid esters.

11. The composition as claimed in claim 1, further comprising a solvent selected from the group consisting of benzyl alcohol, phenyl ethyl alcohol, and chloro butanol.

12. The composition as claimed in claim 1, wherein said adjuvants are selected from the group consisting of stabilizers, antioxidants, preservatives, mucoadhesive agents, buffering agents, absorption enhancers, and pH adjusting agents.

13. The composition according to claim 12, wherein said antioxidant is selected from butylated hydroxytoluene, butylated hydroxyanisole, ascorbic acid and tocopherol, or a combination thereof in the range of 0.01% to 0.2% w/w of the total composition.

14. The composition according to claim 12, wherein said absorption enhancers are selected from macrogol-15-hydroxystearate, sodium glycocholate, sodium caprylate, and a combination thereof.

15. The composition as claimed in claim 1, wherein

the pharmaceutically active substance is selected from the group consisting of olanzapine, ondansetron, risperidone and pharmaceutically acceptable salts thereof;

the mononunsaturated fatty acid is oleic acid; and

the non-ionic surfactant system comprises a mixture of polyethylene glycol, caprylocaproyl macrogol-8 glyceride, and polyoxyethylene (20) sorbitan monolaurate.

16. A method for the treatment of migraine, nausea, cluster headache, schizophrenia, bipolar disorder, vomiting, psychosis, or sleep disorders, said method comprising nasal administration of the composition of claim 15.

17. A process for the preparation of an oil-in-water emulsion composition as claimed in claim 1, comprising the steps of

i) forming an oil phase in the presence of a monounsaturated fatty acid, a polyether surfactant, a macrogolglyceride surfactant, and a polysaccharide surfactant, under stirring at an ambient temperature;

and

ii) adding a therapeutic amount of pharmaceutically active substance to said oil phase, under constant stirring and at an ambient temperature, to encase said active substance, in said monounsaturated fatty acid droplets, said droplets with particle size in the range of 60 to 200 nm, to obtain a homogenous oil phase; and

iii) adding an aqueous medium to said homogenous oil phase, under stirring to obtain the oil-in-water emulsion.

18. The composition of claim 3, wherein said antipsychotics are olanzapine or risperidone, or pharmaceutically acceptable salts thereof.

19. The composition of claim 10, wherein said polyoxyethylene sorbitan fatty acid ester is selected from the group consisting of polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (80) sorbitan monooleate, sorbitan monooleate, and a combination thereof.