# US 8,568,778 B2 · Multiparticulate form of administration, comprising nucleic acid-containing mucoadhesive active ingredients, and method for producing said form of administration

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- Number: US 8,568,778 B2
- Document ID: US8568778B2
- Status: Granted
- Kind: B2
- Application number: 11/721,399
- Filed: 2005-11-05
- Published: 2009-11-12
- Granted: 2013-10-29
- Earliest claimed: 2004-12-10
- Assignees: Evonik Röhm GmbH
- Applicants: Rosario Lizio; Hans-Ulrich Petereit; Dave Trupti; Michael Gottschalk
- Inventors: Rosario Lizio; Hans-Ulrich Petereit; Dave Trupti; Michael Gottschalk
- Web page: https://patentgrep.com/patent/US8568778B2

## CPC

- A61K 9/5138: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/1676: {having a drug-free core with discrete complete coating layer containing drug (adsorbates of liquid drug formulations on inert powders without simultaneous granulation step A61K9/141; with further drug-free outer coating A61K9/5078; drug conjugated to non-active particles A61K47/6921)}
- A61K 9/1694: {resulting in granules or microspheres of the matrix type containing more than 5% of excipient}
- A61K 9/5192: {Processes}
- A61K 31/7088: Compounds having three or more nucleosides or nucleotides
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61K 9/1652: {Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin (homeopathic globules A61K9/1623)}
- 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

## Abstract

The invention relates to an oral, multiparticulate form of administration, comprising pellets in the size ranging from 50 to 2500 $g(m)m which are substantially constituted of a) an inner matrix layer containing nanoparticles that contain a nucleic acid active ingredient and being embedded in a matrix of a polymer having a mucoadhesive effect, and b) an outer film coating, substantially consisting of an anionic polymer or copolymer that is optionally formulated with pharmaceutically conventional adjuvants, especially emollients.

## Claims

### Claim 1

An oral multiparticulate pharmaceutical form comprising pellets having an average diameter in the range from 50 to 2500 μm, the pellets comprising
a) an inner matrix layer comprising nanoparticles, wherein the nanoparticles comprise a nucleic acid active ingredient and are embedded into a matrix of a polymer having a mucoadhesive effect, wherein the matrix may optionally comprise pharmaceutically acceptable excipients, and
b) an outer film coating comprising an anionic polymer or copolymer which may optionally be formulated with pharmaceutically acceptable excipients,
wherein
the multiparticulate pharmaceutical form is formulated so that the pellets are released in the pH range of the stomach, the outer film coating is adjusted through the choice of the anionic polymer or copolymer and its formulation with the excipients and its layer thickness so that the outer film coating dissolves in a pH range from 4.0 to 8.0 in the intestine within 15 to 60 min so that the inner matrix layer is exposed and can bind to the intestinal mucosa and release the nucleic acid active ingredient into the intestinal mucosa, wherein the polymer having a mucoadhesive effect exhibits a mucoadhesive effect of at least ηb=150 to 1000 mPa·s and a water uptake of from 10 to 750% in 15 min in a range of +/−0.5 pH units relative to the pH at which the outer film coating starts to dissolve, and the nucleic acid active ingredient of the nanoparticles in the inner matrix layer is a maximum of 40% by weight of the content of the polymers having a mucoadhesive effect
wherein the nucleic acid active ingredient in the nanoparticles is present in the form of a complex with a cationic substance that is a cationic lipid, a cationic polypeptide or a cationic polymer and an anionic (meth)acrylate copolymer.

### Claim 2 (depends on 1)

The pharmaceutical form according to claim 1, wherein the nanoparticles have a size in the range from 20 to 1000 nm.

### Claim 3 (depends on 1)

The pharmaceutical form according to claim 1, wherein the cationic substance is a cationic lipid, a cationic polypeptide and/or a cationic polymer.

### Claim 4 (depends on 3)

The pharmaceutical form according to claim 3, wherein the cationic polymer is a (meth)acrylate copolymer which has tertiary or quaternary amino groups.

### Claim 5 (depends on 4)

The pharmaceutical form according to claim 4, wherein the (meth)acrylate copolymer comprising free-radical polymerized units of 20 30% by weight methyl methacrylate, 20 30% by weight butyl methacrylate and 60 40% by weight dimethylaminoethyl methacrylate.

### Claim 6 (depends on 1)

The pharmaceutical form according to claim 1, wherein the anionic (meth)acrylate copolymer comprises monomers having anionic groups of from 5 to 60% by weight.

### Claim 7 (depends on 1)

The pharmaceutical form according to claim 1, wherein the anionic (meth)acrylate copolymer comprises
20 to 33% by weight methacrylic acid and/or acrylic acid,
5 to 30% by weight methyl acrylate and
20 to 40% by weight ethyl acrylate and
more than 10 to 30% by weight butyl methacrylate and, if present,
0 to 10% by weight further monomers capable of vinylic copolymerization, wherein the proportions of the monomers add up to 100% by weight, with the proviso that the glass transition temperature of the copolymer according to ISO 11357 2, subsection 3.3.3 (midpoint temperature Tmg) is from 55 to 70° C.

### Claim 8 (depends on 1)

The pharmaceutical form according to claim 1, wherein the anionic (meth)acrylate copolymer has an average molecular weight Mw of 50 000 or less.

### Claim 9 (depends on 1)

The pharmaceutical form according to claim 1, wherein the nanoparticles have an encapsulation with an anionic (meth)acrylate copolymer having an average molecular weight Mw, of 50 000 or less.

### Claim 10 (depends on 1)

The pharmaceutical form according to claim 1, wherein the nucleic acid active ingredient is selected from the group consisting of a single-stranded DNA, double-stranded DNA, RNA, and a DNA-RNA chimera, wherein naturally occurring nucleotides, and/or non-naturally occurring synthetically modified nucleotides or a combination thereof optionally occur.

### Claim 11 (depends on 1)

The pharmaceutical form according to claim 1, wherein the nucleic acid active ingredient comprises a complex of an antibody, which binds specifically to a nucleic acid of the nucleic acid active ingredient, and a cationic substance.

### Claim 12 (depends on 1)

The pharmaceutical form according to claim 1, wherein the outer film coating is cellulose glycolate, cellulose acetate phthalate, cellulose acetate succinate (CAS), cellulose acetate trimeliate (CAT), hydroxypropyl-methylcellulose phthalate (HPMCP, HP50, HP55), hydroxypropylmethylcellulose acetate succinate (HPMCAS-LF, -MF, -HF), polyvinyl acetate phthalate, vinyl acetate-vinylpyrrolidone copolymer, vinyl acetate:crotonic acid 9:1 copolymer and/or shellac.

### Claim 13 (depends on 1)

The pharmaceutical form according to claim 1, wherein the outer film coating is a (meth)acrylate copolymer having a content of monomers having anionic groups of from 5 to 60% by weight.

### Claim 14 (depends on 1)

The pharmaceutical form according to claim 1, wherein the layer thickness of the outer film coating is in the range from 20 to 200 um.

### Claim 15 (depends on 1)

The pharmaceutical form according to claim 1, wherein the inner matrix layer comprises a C10 to C20 fatty acid and/or a C10 to C20 alcohol including their salts, ether, ester or amide derivatives, and/or a lipid, and/or a phospholipids, and/or a lipid-soluble vitamin, and/or a penetration promoter.

### Claim 16 (depends on 1)

The pharmaceutical form according to claim 1, wherein the polymer having a mucoadhesive effect is a chitosan, a (meth)acrylate copolymer consisting of 20 40% by weight methyl methacrylate and 60 to 80% by weight methacrylic acid and/or a cellulose, Na carboxymethylcellulose, a crosslinked and/or uncrosslinked polyacrylic acid, a lectin, an Na alginate, and/or a pectin.

### Claim 17 (depends on 16)

The pharmaceutical form according to claim 16, wherein the inner matrix layer comprises the polymer having a mucoadhesive effect which is a chitosan, which is employed together with an acid or a buffer system which is present in the matrix or in or on a core onto which the matrix is applied.

### Claim 18 (depends on 17)

The pharmaceutical form according to claim 17, wherein the inner matrix layer comprises chitosan and is adjusted to pH 5.0 to 5.5 with an acid or a buffer system, and is combined with an outer film coating which starts to dissolve in the region of pH 6.0 to 8.0.

### Claim 19 (depends on 1)

The pharmaceutical form according to claim 1, wherein a separating layer is applied between the inner matrix layer comprising the nucleic acid active ingredient and the outer film coating layer.

### Claim 20 (depends on 1)

A process for producing a multiparticulate pharmaceutical form of claim 1, comprising:
a) complexing the nucleic acid active ingredient with the cationic substance and the anionic (meth)acrylate copolymer, optionally in the presence of pharmaceutically acceptable excipients,
b) formulating an inner matrix layer comprising the nucleic acid active ingredient in the form of nanoparticles and a polymer having a mucoadhesive effect and, optionally, pharmaceutically acceptable excipients by means of spray application onto a core or by rotagglomeration, precipitation or spray processes without a core to form pre-pellets,
c) applying an outer film coating consisting essentially of an anionic polymer, which may optionally be formulated with pharmaceutically acceptable excipients, by spray application to the pre-pellets to obtain resulting active ingredient-containing enveloped pellets, and
d) processing the resulting pellets to formulate the multiparticulate pharmaceutical form, wherein the resulting pellets are released in the pH range of the stomach.

### Claim 21 (depends on 1)

The multiparticulate pharmaceutical form according to claim 1, wherein the pharmaceutically acceptable excipients are plasticizers.

### Claim 22 (depends on 20)

The process for producing a multiparticulate pharmaceutical form according to claim 20, wherein the pharmaceutically acceptable excipients are plasticizers.

### Claim 23 (depends on 1)

The pharmaceutical form according to claim 1, wherein the pellets have a average diameter of 100 to 2500 μm.

### Claim 24 (depends on 1)

The pharmaceutical form according to claim 1, wherein the outer film coating dissolves in a pH range from 5.5 to 7.8.

### Claim 25 (depends on 1)

The pharmaceutical form according to claim 1, wherein the polymer having a mucoadhesive effect exhibits a water uptake of from 10 to 250% in 15 minutes in a range of +/−0.5 pH unites relative to the pH at which the outer film coating starts to dissolve.

### Claim 26 (depends on 3)

The pharmaceutical form according to claim 3, wherein the cationic substance is a cationic copolymer that has an average molecular weight Mw of 50 000 or less.