# US 8,465,777 B2 · Diffusion-controlled dosage form and method of fabrication including three dimensional printing

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- Number: US 8,465,777 B2
- Document ID: US8465777B2
- Status: Granted
- Kind: B2
- Application number: 13/306,393
- Filed: 2011-11-29
- Published: 2012-07-12
- Granted: 2013-06-18
- Earliest claimed: 2002-05-06
- Assignees: Massachusetts Institute of Technology
- Applicants: Chen-Chao Wang; Jaedeok Yoo; Esteban Bornancini; Willie J Roach; Monica Tejwani
- Inventors: Chen-Chao Wang; Jaedeok Yoo; Esteban Bornancini; Willie J Roach; Monica Tejwani
- Web page: https://patentgrep.com/patent/US8465777B2

## CPC

- A61K 9/00: Medicinal preparations characterised by special physical form {(nuclear magnetic resonance contrast preparations or magnetic resonance imaging contrast preparations A61K49/18; preparations containing radioactive substances A61K51/12)}
- A61K 9/2027: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/2077: {Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets}
- A61K 9/2086: {Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat (active cores with a complete drug-free outer coat A61K9/28)}
- A61K 9/2095: {Tabletting processes}
- A61K 31/137: Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine {or methadone}
- A61P 11/08: Bronchodilators
- A61P 31/04: Antibacterial agents
- B29C 64/153: using layers of powder being selectively joined, e.g. by selective laser sintering or melting
- B33Y 70/00: Materials specially adapted for additive manufacturing
- B33Y 80/00: Products made by additive manufacturing
- 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
- B29C: SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING (making preforms B29B11/00; making laminated products by combining previously unconnected layers which become one product whose layers will remain together B32B37/00 - B32B41/00)
- B33Y: ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING

## Abstract

The invention includes a core-and-shell dosage form or unit in which the core contains API and in which the shell substantially governs the release such as by controlling diffusion of API through the shell. The shell may comprise a release-blocking polymer, and particles of a release-regulating polymer. The shell may be substantially impervious but the release-regulating polymer may become suitable to allow diffusion through it when activated. The core may include a buffer region between the shell and the API-containing portion of the core. The dosage form may include multiple units. The dosage form of the invention is capable of providing a release profile whose time scale can be adjusted by adjusting powder composition, and which may be approximately zero-order release. The invention further includes methods of manufacturing such a dosage form, such as three-dimensional printing.

## Claims

### Claim 1

A method of making a diffusion controlled release dosage form comprising a printed shell and a printed core, the method comprising:
depositing a layer of a powder comprising particles of a release-blocking polymer which is substantially insoluble in water at room temperature but soluble in another solvent, and particles of a release-regulating polymer;
depositing onto the powder in selected places a pattern of a shell binder liquid which comprises a solvent for the release-blocking polymer, thereby forming a portion of the printed shell wherein the powder particles are bound to each other;
depositing onto the powder in selected places a pattern of an Active Pharmaceutical Ingredient-containing liquid, thereby forming a portion of the printed core wherein the powder particles are bound to each other by Active Pharmaceutical Ingredient;
repeating the above steps enough times to manufacture a desired shape, wherein the shell binder liquid and the API-containing liquid differ;
allowing the dosage form to dry; and
separating unbound powder from the dosage form to provide a diffusion controlled release dosage form comprising a printed core and printed shell;
wherein the core includes the same release-blocking polymer and the same release-regulating polymer as contained in the shell, and wherein the core has a core ratio of release-blocking polymer to release-regulating polymer in the core and the shell has a shell ratio of release-blocking polymer to release-regulating polymer in the shell, and the core ratio is substantially the same as the shell ratio.

### Claim 2 (depends on 1)

The method of claim 1 wherein the patterns of selected places in various layers are such that there is a region which received Active Pharmaceutical Ingredient-containing liquid, and that region is completely surrounded by a region which received shell binder liquid.

### Claim 3 (depends on 1)

The method of claim 1 wherein the shell binder liquid is a solvent in which the release-blocking polymer is soluble.

### Claim 4 (depends on 1)

The method of claim 1 wherein the shell binder liquid is a solvent in which both the release-blocking polymer and a plasticizer are soluble.

### Claim 5 (depends on 1)

The method of claim 1 wherein the shell binder liquid is ethanol.

### Claim 6 (depends on 1)

The method of claim 1 wherein the shell binder liquid further includes a plasticizer.

### Claim 7 (depends on 6)

The method of claim 6 wherein the plasticizer is selected from the group consisting of: triethyl citrate, triacetin, diethyl phthalate, acetyltriethyl citrate, acetyltributyl citrate, carboxylic acid esters, and phosphoric acid esters.

### Claim 8 (depends on 1)

The method of claim 1 wherein the shell binder liquid comprises approximately 15 wt % triethyl citrate, together with approximately 85 wt % of an ethanol-water mixture, wherein the ethanol-water mixture comprising approximately 25 wt % water and approximately 75 wt % ethanol.

### Claim 9 (depends on 1)

The method of claim 1 wherein the shell binder liquid further includes a thickening agent suitable to increase the viscosity of the shell binder liquid to a desired value.

### Claim 10 (depends on 1)

The method of claim 1 wherein the depositing of the shell binder liquid is done at a drop volume per voxel volume of at least 0.5 milliliters of shell binder liquid per milliliter of overall volume of a voxel which receives shell binder liquid.

### Claim 11 (depends on 1)

The method of claim 1 wherein the depositing of the shell binder liquid is done at a drop volume per voxel volume of approximately 0.55 milliliters of shell binder liquid per milliliter of overall volume of a voxel which receives shell binder liquid.

### Claim 12 (depends on 1)

The method of claim 1 wherein the depositing of the shell binder liquid is done such that the shell includes at least two adjacent drops or at least two adjacent lines or at least two adjacent powder layers.

### Claim 13 (depends on 1)

The method of claim 1 wherein the release-blocking polymer in the shell has a glass transition temperature, and further including heating the dosage form to a temperature higher than the glass transition temperature.

### Claim 14 (depends on 1)

The method of claim 1 wherein the release-blocking polymer with plasticizer in the shell has a glass transition temperature, and further including heating the dosage form to a temperature higher than the glass transition temperature.

### Claim 15 (depends on 1)

The method of claim 1 wherein the depositing of the shell binder liquid is done at a drop volume per voxel volume of at least 0.5 milliliters of shell binder liquid per milliliter of overall volume of a voxel which receives shell binder liquid, and wherein dispensing of the shell binder liquid is done such that the shell includes at least two adjacent drops or at least two adjacent lines or at least two adjacent powder layers.

### Claim 16 (depends on 15)

The method of claim 15, wherein the release-blocking polymer in the shell has a glass transition temperature, further including heating the dosage form to a temperature higher than the glass transition temperature of the release-blocking polymer in the shell.

### Claim 17 (depends on 1)

The method of claim 1 wherein the Active Pharmaceutical Ingredient-containing liquid further includes a binder substance capable of adhering particles to each other.

### Claim 18 (depends on 1)

The method of claim 1 wherein the Active Pharmaceutical Ingredient-containing liquid does not include a binder substance.

### Claim 19 (depends on 1)

The method of claim 1 wherein the Active Pharmaceutical Ingredient-containing liquid is pseudoephedrine hydrochloride and water.

### Claim 20 (depends on 1)

The method of claim 1 wherein the Active Pharmaceutical Ingredient-containing liquid is approximately 50 wt % pseudoephedrine hydrochloride, approximately 5 wt % polyvinyl pyrrolidone, approximately 0.01 wt % surfactant, balance water.

### Claim 21 (depends on 1)

The method of claim 1 wherein the Active Pharmaceutical Ingredient-containing liquid includes at least one substance from the group consisting of pseudoephedrine hydrochloride, metoprolol, d-chlorpheniramine maleate, chlorpheniramine maleate, diphenhydramine hydrochloride, caffeine, d-brompheniramine maleate, brompheniramine maleate, aminophylline, and orphenadrine citrate.

### Claim 22 (depends on 1)

The method of claim 1, further including allowing the Active Pharmaceutical Ingredient-containing liquid on the powder to at least partially dry, and again depositing Active Pharmaceutical Ingredient-containing liquid onto the powder before deposition of another layer of powder.

### Claim 23 (depends on 1)

The method of claim 1 wherein the release-regulating polymer is selected from the group consisting of: hydroxypropylmethylcellulose, hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, acrylate-methacrylate copolymers, polyethylene glycols, xanthan gum, gellan gum, locust bean gum, guar gum, tragacanth, and sodium alginate.

### Claim 24 (depends on 1)

The method of claim 1 wherein the release-blocking polymer is selected from the group consisting of: a mixture of approximately 80% polyvinyl acetate with approximately 19% poylvinyl pyrrolidone and less than approximately 1% of sodium lauryl sulfate and silica, other polyvinyl acetates, ethyl celluloses, and poly(ethyl acrylate, methyl methacrylate) trimethylammonioethyl methacrylate chloride.

### Claim 25 (depends on 1)

The method of claim 1 wherein the release-blocking polymer is a mixture of approximately 80% polyvinyl acetate with approximately 19% poylvinyl pyrrolidone and less than approximately 1% of sodium lauryl sulfate and silica, and the release-regulating polymer is hydroxypropylmethyl cellulose.

### Claim 26 (depends on 1)

The method of claim 1 wherein the powder comprises a volumetric ratio of release-blocking polymer to release regulating polymer in the range of approximately 80:20 to approximately 40:60.

### Claim 27 (depends on 1)

The method of claim 1, further comprising forming a buffer region of unprinted powder between the core and the shell by leaving some powder, between the core and the shell, that receives neither Active Pharmaceutical Ingredient-containing liquid nor shell binder liquid.

### Claim 28 (depends on 1)

The method of claim 1, further including compressing the dosage form.

### Claim 29 (depends on 1)

The method of claim 1, further including enclosing one or more units in a capsule.

### Claim 30

A method of forming a diffusion controlled release dosage form comprising: a) forming a printed core, which comprises Active Pharmaceutical Ingredient, release-blocking polymer and particles of a release-regulating polymer; and b) coating the core with a printed shell, thereby providing a diffusion controlled release dosage form which comprises a release-blocking polymer and particles of a release-regulating polymer, wherein the ratio of release-blocking polymer to release-regulating polymer in the core and the shell ratio is the same as the ratio of release-blocking polymer to release-regulating polymer in the shell, and the release-blocking polymer and particles of the release-regulating polymer of the core are the same as the release-blocking polymer and particles of the release-regulating polymer of the shell.

### Claim 31 (depends on 30)

The method of claim 30 further comprising forming a buffer region between the printed core and the printed shell by leaving unprinted powder between the printed core and the printed shell, wherein the buffer region comprises release-blocking polymer and particles of a release-regulating polymer.