# US 2019/0167600 A1 · Biomolecule preservation

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- Number: US 2019/0167600 A1
- Document ID: US20190167600A1
- Status: Published application
- Kind: A1
- Application number: 16/322,312
- Filed: 2017-08-03
- Published: 2019-06-06
- Earliest claimed: 2016-08-04
- Assignees: University of Bath
- Applicants: University of Bath
- Inventors: Asel Sartbaeva; Stephen Wells
- Web page: https://patentgrep.com/patent/US20190167600A1

## CPC

- A61K 9/51: Nanocapsules; {Nanoparticles; (nanotubes A61K9/0092; polymeric micelles A61K9/1075; polymersomes A61K9/1273; pure drug nanoparticles A61K9/14; drug nanoparticles with adsorbed surface modifiers A61K9/141; conjugates, e.g. between drug and non-active nanoparticles, A61K47/50; preparations for in vivo diagnosis A61K49/00; with radioactive substances A61K51/00)}
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 9/2036: {Silicones; Polysiloxanes}
- A61K 9/501: {Inorganic compounds}
- A61K 9/5115: {Inorganic compounds}
- A61K 39/00: Medicinal preparations containing antigens or antibodies (materials for immunoassay G01N33/53)
- A61K 39/08: Clostridium, e.g. Clostridium tetani
- A61K 39/39: characterised by the immunostimulating additives, e.g. chemical adjuvants
- A61K 2039/542: {oral/gastrointestinal}
- A61K 2039/60: {characteristics by the carrier linked to the antigen}
- B82Y 5/00: Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
- 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)
- B82Y: SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES

## Abstract

The present invention provides a way to capture a biomolecule such as a protein in one or more layers of covalently bonded amorphous silica, forming a cage or shell which preserves the shape of the protein and prevents denaturation caused by heat and/or aging and/or non-physiological conditions, through unfolding and loss of secondary and/or higher order structure.

## Claims

### Claim 1

A biomolecule enveloped with silica.

### Claim 2 (depends on 1)

The biomolecule enveloped with silica according to claim 1, wherein the silica envelope separates the biomolecule from surrounding conditions.

### Claim 3 (depends on 2)

The biomolecule enveloped with silica according to claim 2, wherein the surrounding conditions are denaturing conditions, optionally selected from heat, acid pH and aging; or wherein the surrounding conditions are other molecules.

### Claim 4

(canceled)

### Claim 5 (depends on 2)

The biomolecule enveloped with silica according to claim 2, wherein separation from surrounding conditions prevents the biomolecule from performing its function.

### Claim 6 (depends on 1)

The biomolecule enveloped with silica according to claim 1, wherein the silica envelope is substantially continuous; or wherein the silica envelope is water impermeable; or wherein the silica envelope comprises covalently bonded amorphous silica deposited around the biomolecule; or wherein the silica envelope comprises one or more layers of covalently bonded amorphous silica; or wherein the silica envelope is amorphous nano silica; or wherein the silica envelope prevents denaturation of the biomolecule.

### Claim 7

(canceled)

### Claim 8

(canceled)

### Claim 9

(canceled)

### Claim 10

(canceled)

### Claim 11

(canceled)

### Claim 12 (depends on 1)

The biomolecule enveloped with silica according to claim 1, wherein the biomolecule has secondary structure, optionally has tertiary structure and further optionally has quaternary structure; or wherein the biomolecule is a protein or polypeptide; or wherein the biomolecule is a protein vaccine or a virus-like particle; or wherein the biomolecule is an antibody or fragment thereof, or is an enzyme; or wherein the biomolecule is a carbohydrate or a polysaccharide, optionally wherein the biomolecule comprises a bacterial capsular polysaccharide.

### Claim 13

(canceled)

### Claim 14

(canceled)

### Claim 15

(canceled)

### Claim 16

(canceled)

### Claim 17 (depends on 1)

A powder or a suspension comprising a plurality of biomolecules enveloped with silica according to claim 1.

### Claim 18 (depends on 1)

An oral vaccine comprising the biomolecule enveloped with silica according to claim 1.

### Claim 19 (depends on 1)

A gastric-resistant oral dosage form of a biomolecule comprising the biomolecule enveloped with silica according to claim 1, optionally wherein the envelope comprises covalently bonded amorphous silica deposited around the biomolecule.

### Claim 20

(canceled)

### Claim 21

(canceled)

### Claim 22 (depends on 1)

A biomolecule enveloped with silica according to claim 1 for use in therapy or for use in a method of vaccination.

### Claim 23

(canceled)

### Claim 24

A method of enveloping a biomolecule with silica comprising:
a) hydrolysing a silica starting material to produce a hydrolysed silica precursor,
b) contacting the hydrolysed silica precursor with an aqueous solution comprising the biomolecule,
wherein the silica precursor precipitates about the biomolecule, optionally wherein the method occurs in aqueous phase; or wherein the aqueous solution comprising the biomolecule further comprises a buffer and has a pH≥6; or wherein the aqueous solution comprising the biomolecule and the buffer and has a pH in the range of 6.5≤pH≥7.5, optionally wherein the pH is about 7; wherein the aqueous solution comprising the biomolecule has a concentration of the biomolecule which is less than that which causes spontaneous aggregation of the biomolecule.

### Claim 25

(canceled)

### Claim 26 (depends on 24)

A method according to claim 24, wherein the silica starting material contains silicon atoms coordinated by labile organic groups, optionally wherein the silicon atoms are coordinated by alkoxide groups or derivatives of alkoxide groups, further optionally wherein the silicon atoms are coordinated by methoxy, ethoxy, propyoxy, butoxy groups or derivates thereof; or wherein the silica starting material contains tetra-ethoxy-orthosilicate (TEOS); or wherein the hydrolysed silica precursor comprises
a) silica monomers, and/or
b) hydrolysed alkoxysilane, and preferably hydrolysed TEOS.

### Claim 27

(canceled)

### Claim 28 (depends on 24)

The method according to claim 24, wherein hydrolysing a silica starting material to produce a hydrolysed silica precursor occurs at acidic pH, optionally wherein the acidic pH≤4.0, 3.5, 3.0, 2.5 or 2.0.

### Claim 29

(canceled)

### Claim 30

(canceled)

### Claim 31 (depends on 24)

The method according to claim 24, wherein the hydrolysed silica precursor in aqueous solution forms a single phase and/or has a viscosity similar to water.

### Claim 32

(canceled)

### Claim 33

(canceled)

### Claim 34

(canceled)

### Claim 35 (depends on 24)

The method according to claim 24, wherein contacting the hydrolysed silica precursor with an aqueous solution comprising the biomolecule occurs at a pH ≥6; or wherein the contacting occurs at a pH in the range of 6.5≤pH≥7.5, optionally wherein the pH is about 7.

### Claim 36

(canceled)

### Claim 37 (depends on 24)

The method according to claim 24, wherein the silica precursor precipitates about the biomolecule to form covalently bonded amorphous silica about the biomolecule; or wherein enveloping the biomolecule with silica prevents denaturation of the biomolecule.

### Claim 38

(canceled)

### Claim 39

A method of reducing biomolecule denaturation in non-physiological conditions comprising enveloping the biomolecule with silica, the enveloping comprising contacting a hydrolysed silica precursor with an aqueous solution comprising the biomolecule, wherein the silica precursor precipitates about the biomolecule; or
a method of transporting and/or storing a biomolecule, comprising
a) obtaining the biomolecule enveloped with silica
b) transporting the biomolecule from a first location to a second location and/or storing the biomolecule,
wherein at least a portion of the transporting and/or storing occurs in the absence of a cold-chain; or
a method of providing a gastric resistant coating to a biomolecule comprising contacting a hydrolysed silica precursor with an aqueous solution comprising the biomolecule, wherein the silica precursor precipitates about the biomolecule to form the gastric resistant coat.

### Claim 40

(canceled)

### Claim 41

(canceled)

### Claim 42 (depends on 39)

The method according to claim 39, wherein the biomolecule is a therapeutic agent.

### Claim 43

A method of vaccination comprising administering to a subject in need thereof, a vaccine comprising a biomolecule enveloped with silica; or
a method of vaccination comprising administration to a subject in need thereof, a biomolecule with secondary or higher order structure, by
a) oral administration of the biomolecule enveloped with silica, or
b) release of the biomolecule from a silica envelope followed by re-formulation of the biomolecule and injection into the subject.

### Claim 44 (depends on 43)

The method according to claim 43, wherein the silica envelope separates the biomolecule from surrounding conditions; or wherein the envelope comprises covalently bonded amorphous silica deposited around the biomolecule.

### Claim 45

(canceled)

### Claim 46 (depends on 43)

The method according to claim 43, wherein the biomolecule is a protein vaccine or a virus-like particle; or wherein the biomolecule is an antibody or fragment thereof, or an enzyme; or wherein the biomolecule is a carbohydrate or a polysaccharide, optionally wherein the biomolecule comprises a bacterial capsular polysaccharide.

### Claim 47

(canceled)

### Claim 48

(canceled)

### Claim 49 (depends on 43)

The method according to claim 43, wherein the administration is oral administration.

### Claim 50

(canceled)

### Claim 51

A method of releasing a biomolecule from an envelope of silica deposited around the biomolecule, comprising contacting the biomolecule and its envelope of silica with a release solution comprising fluoride ions at acidic pH; or
a method of enveloping a biomolecule with silica and subsequently releasing the biomolecule from the silica envelope, comprising:
a) hydrolysing a silica starting material to produce an aqueous solution of hydrolysed silica precursor,
b) contacting the hydrolysed silica precursor with an aqueous solution comprising the biomolecule, wherein the silica precursor precipitates about the biomolecule, and
c) contacting the biomolecule and its silica envelope with a release solution comprising fluoride ions at acidic pH.

### Claim 52 (depends on 51)

The method according to claim 51, further comprising agitation of the mixture.

### Claim 53 (depends on 51)

The method according to claim 51, wherein the release solution comprises a fluoride ion concentration of from about 75 mM to about 150 mM, optionally the fluoride ion concentration is from about 75 mM to about 125 mM, further optionally the fluoride ion concentration is from about 85 mM to about 115 mM, or wherein the release solution has a pH of less than or equal to 6.0, preferably is less than 5.5, or is less than 5.0; or wherein the pH of the release solution is adjusted to about pH 5.0 or about 4.0.

### Claim 54

(canceled)

### Claim 55

(canceled)

### Claim 56 (depends on 51)

The method according to claim 51, wherein the biomolecule is a therapeutic agent.

### Claim 57 (depends on 51)

The method according to claim 51, wherein the silica envelope separates the biomolecule from surrounding conditions.

### Claim 58

(canceled)