# US 11,896,575 B2 · Transdermal formulation for delivery of hydrophobic compounds and process for the preparation thereof

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 11,896,575 B2
- Document ID: US11896575B2
- Status: Granted
- Kind: B2
- Application number: 16/756,689
- Filed: 2018-10-16
- Published: 2020-07-30
- Granted: 2024-02-13
- Earliest claimed: 2017-10-16
- Assignees: Delivra Inc.
- Applicants: Delivra Inc.
- Inventors: Joseph Gabriele; Mikaela Teris
- Web page: https://patentgrep.com/patent/US11896575B2

## CPC

- A61K 31/658: {o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol}
- A61K 9/0014: {Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00)}
- A61K 9/0031: {Rectum, anus}
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 9/006: {Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays}
- A61K 9/107: Emulsions {; Emulsion preconcentrates; Micelles (composition of emulsions A61K47/00)}
- A61K 31/137: Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine {or methadone}
- A61K 31/167: having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
- A61K 31/445: Non condensed piperidines, e.g. piperocaine
- A61K 31/485: Morphinan derivatives, e.g. morphine, codeine
- A61K 47/14: Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
- A61K 47/22: Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
- A61K 47/24: containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
- A61K 47/30: Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K 47/36: Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K 47/38: Cellulose; Derivatives thereof
- 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)
- A61K 47/46: Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
- 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)

## Abstract

The present application includes a transdermal base formulation useful for example, for the transdermal delivery of active pharmaceutical ingredients along with a process for preparation thereof. In particular, the transdermal base formulation comprises: (a) an aqueous phase comprising water and at least one emulsion stabilizer; (b) an oil phase comprising at least one emulsifier, at least one emulsion stabilizer, at least one emollient comprising at least one flavonoid, at least one other emollient, and a terpene-rich natural butter; (c) an external phase comprising at least one terpene-rich extract or oil, at least one penetration enhancer and a phospholipid-complexed flavonoid; and optionally (d) at least one preservative phase.

## Claims

### Claim 1

A transdermal emulsion formulation comprising:
(a) an aqueous phase comprising water and at least one emulsion stabilizer selected from natural polymers, gums and synthetic polymers, and mixtures thereof; wherein the natural polymers are selected from alginic acid, cellulose, and scleroglucans, and mixtures thereof, wherein the gums are selected from xanthan gum, tara gum, guar gum and arabic gum, and mixtures thereof, and wherein the synthetic polymers are selected from polyacrylates, polyisobutenes and polysorbates, and mixtures thereof, and wherein the at least one emulsion stabilizer in the aqueous phase is present in an amount of about 0.1 wt % to about 1 wt %;
(b) an oil phase comprising:
at least one emulsifier selected from oil-soluble fatty acid esters or mixtures of fatty acid esters in which the fatty acid esters have a fatty acid composition similar to the fatty acid composition of skin, wherein the oil-soluble fatty acid esters or mixture of fatty acid esters are C14-C26-fatty acids esterified with a fatty acid alcohol selected from cetyl alcohol, cetaryl alcohol, lauryl alcohol, stearyl alcohol, myristyl alcohol and oleyl alcohol or with a sugar alcohol selected from sorbitol, glycerol, mannitol, inositol, xylitol, erythritol, threitol, arabitol, ribitol, or mixtures thereof, wherein the at least one emulsifier in the oil phase is present in an amount of about 2 wt % to about 8 wt %;
at least one emulsion stabilizer selected from one or more waxes, wherein the at least one emulsion stabilizer in the oil phase is present in an amount of about 1 wt % to about 10 wt %;
at least one emollient comprising at least one flavonoid, wherein the at least one emollient is a natural oil or extract from citrus, Ginkgo biloba, tea, wine, cacao, onion, kale, parsley, red beans, broccoli, endive, celery, cranberries, blackberries, red raspberries, blackcurrants, acai, blueberries, bilberries, milk thistle, apples, hawthorn, Echinacea, grapes, and/or soy, or wherein the at least one emollient comprising at least one flavonoid in the oil phase is a natural oil or extract from the genera Rubus, Ribes, Argania, Nymphaea, Peucedanum or Imperatoria, Sambucus, Calendula, Butea, Citrus (e.g. lime), or species or subspecies thereof, and wherein the at least one emollient comprising at least one flavonoid in the oil phase is present in an amount of about 3 wt % to about 15 wt %;
at least one other emollient selected from octyl palmitate, isopropyl stearate, isopropyl palmitate, octyl dodecanol, or mixtures thereof, wherein the at least one other emollient in the oil phase is present in an amount of about 1 wt % to about 10 wt %; and
a terpene-rich natural butter, which is a terpene-rich seed butter, wherein the terpene-rich natural butter in the oil phase is present in an amount of about 1 wt % to about 10 wt %;
wherein the oil and aqueous phase form an emulsion;
(c) an external phase comprising:
at least one terpene-rich extract or oil selected from essential oils or extracts from fruits vegetables, herbs, spices, legumes, leaves, seeds, or mixtures thereof, wherein the at least one terpene-rich extract or oil is present in an amount of about 0.1 wt % to about 10 wt %;
at least one penetration enhancers selected from a glycol, dimethyl isosorbide, or a mixture of glycols and/or dimethylisosorbide, wherein the at least one penetration enhancer is present in an amount of about 1 wt % to about 5 wt %;
a phospholipid-complexed flavonoid, wherein the phospholipid is selected from phosphatidylcholine, phosphatidylethanolamine, phosphatidylinostinol, phosphatidylserine, or mixtures thereof, and wherein the flavonoid is selected from quercetin, myrcetin, apigenin, rutin, or mixtures thereof, wherein the phospholipid- complexed flavonoid is present in an amount of about 1 wt % to about 4 wt %; and
a hydrophobic active agent, wherein the hydrophobic active agent comprises:
nabilone present in an amount of about 0.01 wt % to about 1 wt %;
buprenorphine present in an amount of about 0.001 wt % to about 1 wt %;
bupivacaine present as hydrochloride in an amount of about 0.1 wt % to about 5 wt %;
lidocaine present in an amount of about 0.1 wt % to about 10 wt %;
a combination of bupivacaine, lidocaine and epinephrine, wherein the bupivacaine is present as hydrochloride in an amount of about 0.1 wt % to about 5 wt %, the lidocaine is present in an amount of about 0.1 wt % to about 10 wt %, and the epinephrine is present in an amount of about 0.001 wt % to about 1 wt %;
a synthetic cannabinoid present in an amount of about 0.1 wt % to about 5 wt %.
one or more plant-derived cannabinoids, each present in an amount of about 0.1 wt % to about 5 wt %, optionally wherein the one or more plant-derived cannabinoid is THC, CBD, or a combination of THC and CBD; and
optionally,
(d) at least one preservative phase.

### Claim 2 (depends on 1)

The transdermal formulation of claim 1, wherein the formulation comprises at least one preservative.

### Claim 3 (depends on 1)

The transdermal formulation of claim 1, wherein the formulations further comprise additional ingredients selected from one or more of pH adjusters or buffering agents, further solvents, solubilizers, chelating agents, pigments, fragrances, humectants and/or solubilizers.

### Claim 4 (depends on 1)

The transdermal formulation of claim 1, wherein the terpene-rich natural butter is mango butter.

### Claim 5 (depends on 1)

The transdermal formulation of claim 1, wherein the terpene- rich extract or oil is an essential oil or an extract from mango, hops, clove, myrtle lemon, black pepper, fennel, and mixtures thereof.

### Claim 6 (depends on 1)

A method for the transdermal administration of one or more hydrophobic active agents comprising administering an effecting amount of a formulation of claim 1 to a subject in need thereof.

### Claim 7 (depends on 1)

A method for the buccal or rectal administration of one or more hydrophobic active agents comprising administering an effecting amount of a formulation of claim 1 to a subject in need thereof.

### Claim 8 (depends on 1)

The transdermal formulation of claim 1, wherein the at least one emulsion stabilizer in the aqueous phase is present in an amount of about 0.2 wt % to about 0.8 wt %.

### Claim 9 (depends on 1)

The transdermal formulation of claim 1, wherein the at least one emulsifier in the oil phase is present in an amount of about 4 wt % to about 6 wt %.

### Claim 10 (depends on 1)

The transdermal formulation of claim 1, wherein the at least one emulsion stabilizer in the oil phase is present in an amount of about 2 wt % to about 8 wt %.

### Claim 11 (depends on 1)

The transdermal formulation of claim 1, wherein:
the at least one emollient comprising at least one flavonoid in the oil phase is present in an amount of about 5 wt % to about 12 wt %; or
the at least one other emollient in the oil phase is present in an amount of about 3 w% to about 5 w%.

### Claim 12 (depends on 1)

The transdermal formulation of claim 1, wherein terpene-rich natural butter in the oil phase is present in an amount of about 2 w% to about 5 w%, or about 3 w%.

### Claim 13 (depends on 1)

The transdermal formulation of claim 1, wherein the penetration enhancer is ethoxydiglycol.

### Claim 14 (depends on 1)

The transdermal formulation of claim 1, wherein:
the at least one terpene-rich extract or oil is present in an amount of about 0.2 wt % to 5 wt %; or
the penetration enhancer is present in an amount of about 1 wt % to about 2 wt %; or
the phospholipid-complexed flavonoid is present in an amount of about 1.5 w% to about 2.5 w%.

### Claim 15 (depends on 1)

The transdermal formulation of claim 1, wherein:
the hydrophobic active agent is nabilone present in an amount of about 0.05 wt % to about 0.5 wt %, or about 0.05 wt %;
the hydrophobic active agent is buprenorphine present in an amount of about 0.01 wt % to about 0.05 wt %, or about 0.02 wt %;
the hydrophobic active agent is bupivacaine present as hydrochloride in an amount of about 1.0 w t% to about 3.0 wt %, or about 2.0 wt %;
the hydrophobic active agent is lidocaine present in an amount of about 2.0 wt % to about 8.0 wt %, or about 5.0 wt %;
a combination of bupivacaine, lidocaine and epinephrine, wherein the bupivacaine is present as hydrochloride in an amount of about 1.0 wt % to about 3.0 wt %, or about 2.0 wt %, the lidocaine is present in an amount of a about 2.0 wt % to about 8.0 wt %, or about 5.0 wt %, and the epinephrine is present in an amount of about 0.01 wt % to about 0.05 wt %, or about 0.05 wt %; or
the hydrophobic active agent is the synthetic cannabinoid present in an amount of about 1.0 wt % to about 3.0 wt %, or about 1.5 wt %.

### Claim 16 (depends on 1)

The transdermal formulation of claim 1, wherein:
the transdermal formulation further comprises an oily vehicle comprising mono-, di- and triglycerides,
optionally wherein the oily vehicle is obtained by alcoholysis between glycerol and refined corn oil, followed by winterization to remove saturated mono-, di- and triglycerides;
optionally wherein the oily vehicle comprises:
i) about 25-75% (or about 32-52%) of monoglycerides of oleic and linoleic acid;
ii) about 25-75% (or about 40-55%) of diglycerides of oleic and linoleic acid; and
iii) about 1-50% (or about 5-20%) of triglycerides of oleic and linoleic acid; or the hydrophobic active agent is pre-solubilized in an oil formulation, the oil formulation comprising:
i) the hydrophobic active agent;
ii) an oily vehicle comprising mono-, di- and triglycerides;
iii) at least one polar oil, optionally argan oil, sunflower oil, olive oil, avocado oil or jojoba oil; and
iv) the penetration enhancer; or
the hydrophobic active agent is pre-solubilized in an oil formulation, the oil formulation comprising:
i) the hydrophobic active agent comprises a cannabinoid or terpene, wherein the cannabinoid is CO2 extracted, in an amount between about 5-10% (w/w), or about 6.6%;
ii) an oily vehicle comprising mono-, di- and triglycerides in an amount between about 20%-60%, or about 40.0%;
iii) a polar oil, optionally argan oil, sunflower oil, olive oil, avocado oil or jojoba oil, present in an amount between about 25%-50%, or about 33.4%; and
iv) the penetration enhancer, present in an amount between about 10%-30%, or about 20.0%.

### Claim 17 (depends on 16)

The transdermal formulation of claim 16, wherein the penetration enhancer is 2-(2-Ethoxyethoxy)ethanol.

### Claim 18 (depends on 1)

The transdermal formulation of claim 1, wherein:
the at least one emulsion stabilizer in the aqueous phase comprises xanthan gum;
the at least one emulsion stabilizer in the oil phase comprises one or more plant waxes derived from olives or from palm;
the at least one other emollient in the oil phase comprises isopropyl palmitate;
the terpene-rich natural butter in the oil phase is mango butter; the at least one terpene-rich extract or oil is an essential oil or an extract from mango, hops, clove, myrtle lemon, black pepper, fennel, or a combination of two or more thereof; and
the at least one penetration enhancer comprises ethoxydiglycol.

### Claim 19 (depends on 1)

The transdermal emulsion formulation of claim 1, wherein:
the at least one emulsion stabilizer in the aqueous phase is present in an amount of about 0.2 wt % to about 0.8 wt %;
the at least one emulsifier in the oil phase is present in an amount of about 4 wt % to about 6 wt %;
the at least one emulsion stabilizer in the oil phase is present in an amount of about 2 wt % to about 8 wt %;
the at least one emollient comprising at least one flavonoid in the oil phase is present in an amount of about 5 wt % to about 12 wt %;
the at least one other emollient in the oil phase is present in an amount of about 3 wt % to about 5 wt %;
the terpene-rich natural butter in the oil phase is present in an amount of about 2 wt % to about 5 wt %;the at least one terpene-rich extract or oil is present in an amount of about 0.2 wt % to about 5 wt %;
the at least one penetration enhancer is present in an amount of about 1 wt % to about 2 wt %; and
the phospholipid-complexed flavonoid is present in an amount of about 1.5 wt % to about 2.5 wt %.

### Claim 20 (depends on 1)

The transdermal emulsion formulation of claim 1, wherein the hydrophobic active agent is THC, CBD, or a combination of THC and CBD present at a ratio of between about 0.1:5.0 to 5.0:0.1, or about 1:1.