# US 2013/0157992 A1 · Sustained drug release and improved product stability using non-covalent particle coating methods

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- Number: US 2013/0157992 A1
- Document ID: US20130157992A1
- Status: Published application
- Kind: A1
- Application number: 13/721,733
- Filed: 2012-12-20
- Published: 2013-06-20
- Earliest claimed: 2011-12-20
- Inventors: Keith R. Latham
- Web page: https://patentgrep.com/patent/US20130157992A1

## CPC

- A61K 9/14: Particulate form, e.g. powders, {Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles (microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51)}
- A61K 9/146: {with organic macromolecular compounds}
- A61K 9/2031: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers}
- A61K 9/2054: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- A61K 9/2063: {Proteins, e.g. gelatin}
- 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 invention relates to improved methods of making compositions and compositions made by these methods having improved stability and/or extended release of an active agent or drug upon administration. These compositions may generally comprise an active agent or drug non-covalently immobilized or bound to an excipient substrate. The active agent or drug may include a wide variety of drugs. Binding of the active agent or drug to the substrate may be achieved by evaporating a solvent containing the active agent dissolved therein or by triggering co-precipitation by addition of a precipitating solvent. Additional steps of vacuum removal of surrounding atmosphere and replacement with inert gas may provide additional stability. Present methods and compositions also facilitate manufacturing of drug products and may make these processes safer in some cases. The present invention further provides improved methods of treatment or administration, which may take advantage of improvements with present compositions.

## Claims

### Claim 1

A method comprising the following steps:
(a) dissolving an active agent or drug in a solvent to form a solution containing the active agent or drug; and
(b) evaporating the solvent from the solution until a substrate powder is formed, the substrate powder comprising the active agent or drug non-covalently bound to a substrate, wherein the substrate is a polymer or crystalline excipient.

### Claim 2 (depends on 1)

The method of claim 1, wherein the active agent or drug is homogeneously distributed throughout the substrate powder formed in step (b).

### Claim 3 (depends on 1)

The method of claim 1, wherein the evaporating step (b) comprises subjecting the solution to a reduced pressure or vacuum.

### Claim 4 (depends on 3)

The method of claim 3, wherein the evaporating step (b) comprises subjecting the solution to an elevated temperature.

### Claim 5 (depends on 1)

The method of claim 1, wherein the substrate comprises one or more of the following excipients: cellulose, polydextran, silica, silicate, activated carbon, gelatin, collagen, polysaccharide, polypeptide, starch and polyethylene glycol.

### Claim 6 (depends on 1)

The method of claim 1, wherein the solvent is an anhydrous solvent.

### Claim 7 (depends on 6)

The method of claim 6, wherein the solvent comprises one or more of the following:
tetrahydrofuran, hexane, acetone, ethanol, methanol, methyl ethyl ketone, and ethyl acetate.

### Claim 8 (depends on 1)

The method of claim 1, wherein the solvent has a boiling point of about 100° C. or less.

### Claim 9 (depends on 1)

The method of claim 1, wherein the solvent comprises water.

### Claim 10 (depends on 1)

The method of claim 1, further comprising:
(c) adding the substrate to the solvent,
wherein step (c) is performed before or during the dissolving step (a).

### Claim 11 (depends on 10)

The method of claim 10, wherein the substrate is dissolved in the solvent prior to step (b).

### Claim 12 (depends on 1)

The method of claim 1, further comprising:
(c) adding the substrate to the solvent,
wherein step (c) is performed after the dissolving step (a).

### Claim 13 (depends on 12)

The method of claim 12, wherein the substrate is dissolved in the solvent prior to step (b).

### Claim 14 (depends on 1)

The method of claim 1, wherein the solvent comprises two or more solvents.

### Claim 15 (depends on 1)

The method of claim 1, wherein step (a) further comprises dissolving a second active agent or drug in the solvent, the second active agent or drug becoming non-covalently bound to the substrate in step (b).

### Claim 16 (depends on 15)

The method of claim 15, wherein the active agent or drug is triiodothyronine (T3) and the second active agent or drug is thyroxine (T4).

### Claim 17 (depends on 1)

The method of claim 1, further comprising:
(d) adding a capping agent to the solvent,
wherein step (d) is performed prior to the evaporating step (b).

### Claim 18 (depends on 17)

The method of claim 17, wherein step (d) is performed before or during the dissolving step (a).

### Claim 19 (depends on 17)

The method of claim 17, wherein the capping agent is dissolved in the solvent prior to step (b) and becomes non-covalently bound to the substrate in step (b).

### Claim 20 (depends on 17)

The method of claim 17, wherein the capping agent comprises one or more of the following: magnesium stearate (Mg stearate), steric acid, or stearyl fumarate.

### Claim 21 (depends on 17)

The method of claim 17, wherein the capping agent comprises a polypeptide.

### Claim 22 (depends on 21)

The method of claim 21, wherein the capping agent comprises polyglutamic acid.

### Claim 23 (depends on 1)

The method of claim 1, further comprising:
(e) dissolving a second active agent or drug in a second solvent to form a second solution; and
(f) evaporating the second solvent from the second solution to form a second substrate powder comprising each of the active agent or drug and the second active agent or drug non-covalently bound to the substrate.

### Claim 24 (depends on 23)

The method of claim 23, further comprising:
(g) adding the substrate powder to the second solvent,
wherein step (g) is performed after the dissolving step (e) but prior to the evaporating step (f).

### Claim 25 (depends on 23)

The method of claim 23, further comprising:
(g) adding the substrate powder to the second solvent,
wherein step (g) is performed before or during the dissolving step (e).

### Claim 26 (depends on 1)

The method of claim 1, further comprising:
(h) dissolving a capping agent in a second solvent to form a second solution; and
(i) evaporating the second solvent from the second solution to form a second substrate powder comprising each of the active agent or drug and the capping agent non-covalently bound to the substrate.

### Claim 27 (depends on 26)

The method of claim 26, further comprising:
(j) adding the substrate powder to the second solvent,
wherein step (j) is performed prior to the evaporating step (i).

### Claim 28 (depends on 1)

The method of claim 1, wherein the active agent or drug is an iodinated L-thyronine congener.

### Claim 29 (depends on 28)

The method of claim 28, wherein the active agent or drug is 3,5,3′-triiodo-L-thyronine (T3).

### Claim 30 (depends on 29)

The method of claim 29, wherein the substrate is cellulose.

### Claim 31 (depends on 29)

The method of claim 29, wherein the solvent is an anhydrous organic solvent.

### Claim 32 (depends on 28)

The method of claim 28, wherein the active agent or drug is L-thyroxine (T4).

### Claim 33 (depends on 32)

The method of claim 32, wherein the solvent is an anhydrous organic solvent.

### Claim 34 (depends on 1)

The method of claim 1, further comprising:
(k) dissolving a second active agent or drug in a second solvent to form a second solution; and
(l) evaporating the second solvent from the second solution to form a second substrate powder comprising the second active agent or drug non-covalently bound to a second substrate.

### Claim 35 (depends on 34)

The method of claim 34, further comprising:
(m) combining the substrate powder and the second substrate powder and optionally adding one or more excipients to form a final formulation.

### Claim 36 (depends on 1)

The method of claim 1, further comprising:
(n) replacing the atmosphere surrounding the substrate powder with an inert gas.

### Claim 37 (depends on 36)

The method of claim 36, wherein the inert gas is one or more of: Nitrogen (N2), Carbon Dioxide (CO2), Argon (Ar) or Xenon (Xe).

### Claim 38 (depends on 36)

The method of claim 36, further comprising:
(o) repeating step (n).

### Claim 39 (depends on 1)

The method of claim 1, further comprising:
(p) combining one or more excipients with the substrate powder to form a final formulation.

### Claim 40 (depends on 1)

The method of claim 1, further comprising:
(q) combining one or more active agents or drugs with the substrate powder to form a final formulation.

### Claim 41 (depends on 40)

The method of claim 40, wherein step (q) further comprises combining one or more excipients with the substrate powder to form the final formulation.

### Claim 42 (depends on 1)

The method of claim 1, further comprising:
(r) forming the substrate powder into one or more dosage forms.

### Claim 43 (depends on 42)

The method of claim 42, wherein step (r) comprises compressing the substrate powder into one or more tablets.

### Claim 44 (depends on 42)

The method of claim 42, further comprising:
(s) placing the one or more dosage forms into a container; and
(t) filling the container with an inert gas.

### Claim 45 (depends on 39)

The method of claim 39, further comprising:
(r) forming the final formulation into one or more dosage forms.

### Claim 46 (depends on 45)

The method of claim 45, wherein step (r) comprises compressing the final formulation into one or more tablets.

### Claim 47 (depends on 40)

The method of claim 40, further comprising:
(r) forming the final formulation into one or more dosage forms.

### Claim 48

A method comprising the following steps:
(a) dissolving an active agent or drug in a dispersing solvent to form a solution containing the active agent or drug;
(b) co-precipitating the active agent or drug and a substrate by adding a precipitating solvent to the solution to form a precipitate, the precipitate comprising the active agent or drug non-covalently bound to the substrate, wherein the substrate is a polymer or crystalline excipient.

### Claim 49 (depends on 48)

The method of claim 48, further comprising:
(c) removing most of the dispersing solvent and the precipitating solvent; and
(d) drying the precipitate to form a substrate powder.

### Claim 50 (depends on 49)

The method of claim 49, wherein the removing step (c) comprises:
(e) centrifuging the solvents and precipitate to form a pellet of the precipitate; and
(f) aspirating most of the dispersing solvent and the precipitating solvent.

### Claim 51 (depends on 49)

The method of claim 49, wherein the drying step (d) comprises subjecting the precipitate to reduced or vacuum pressure.

### Claim 52 (depends on 1)

A composition comprising the substrate powder of claim 1.

### Claim 53 (depends on 39)

A composition comprising the final formulation of claim 39.

### Claim 54 (depends on 42)

A composition comprising the one or more dosage forms of claim 42.

### Claim 55

A method comprising the following steps:
administering a pharmaceutical composition to an individual, the pharmaceutical composition comprising a substrate powder,
wherein the substrate powder comprises an active agent or drug non-covalently bound to a substrate, the substrate being a polymer or crystalline excipient.

### Claim 56 (depends on 55)

The method of claim 55, wherein the substrate powder is formed by dissolving the active agent or drug in a solvent to form a solution and evaporating the solvent to cause the active agent or drug to bind to the substrate present in the solution.

### Claim 57 (depends on 55)

The method of claim 55, wherein the individual has or is experiencing hypothyroidism, myxedema, or a myxedema coma.

### Claim 58 (depends on 55)

The method of claim 55, wherein the active agent or drug is an iodinated thyronine congener.

### Claim 59 (depends on 58)

The method of claim 58, wherein the active agent or drug is 3,5,3′-triiodo-L-thyronine (T3).

### Claim 60 (depends on 59)

The method of claim 59, wherein the administering step consists of administering the pharmaceutical composition only once per day, and wherein the administering step is repeated daily, the amount per single daily dosage of T3 in the pharmaceutical composition being in a range from about 10 μg to about 50 μg.

### Claim 61 (depends on 60)

The method of claim 60, wherein the individual is maintained in a euthyroid state as a result of repeatedly administering the daily dosages of T3.

### Claim 62 (depends on 60)

The method of claim 60, wherein the amount per single daily dosage of T3 is an amount effective to maintain the individual in a euthyroid state.

### Claim 63 (depends on 60)

The method of claim 60, further comprising:
determining the levels of one or more gene products present in a sample or biopsy taken from the individual, the one or more gene products being downstream targets of T3; and
adjusting the single daily dosage of T3 based on the determined levels of the one or more gene products.

### Claim 64 (depends on 63)

The method of claim 63, wherein the one or more gene products include one or both of transferrin and sex hormone binding globulin (SHBG).

### Claim 65 (depends on 60)

The method of claim 60, further comprising:
adjusting the single daily dosage of T3 based on the clinical presentation of the individual.

### Claim 66 (depends on 58)

The method of claim 58, wherein the active agent or drug is L-thyroxine (T4).

### Claim 67 (depends on 66)

The method of claim 66, wherein the administering step consists of administering the pharmaceutical composition only once per day, and wherein the administering step is repeated daily, the amount per single daily dosage of T4 in the pharmaceutical composition being in a range from about 50 μg to about 200 μg.