# US 12,005,156 B2 · Berberine/mineralized collagen-based composite membrane and preparation method and application thereof

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- Number: US 12,005,156 B2
- Document ID: US12005156B2
- Status: Granted
- Kind: B2
- Application number: 17/413,390
- Filed: 2021-04-02
- Published: 2023-11-09
- Granted: 2024-06-11
- Earliest claimed: 2020-11-23
- Assignees: Weifang Medical University
- Applicants: Weifang Medical University
- Inventors: Weifen Zhang; Jian Zhang; Jingjing Zhang; Dejun Ding; Xiuwen Guan; Linlin Hu; Yuhan Zhang
- Web page: https://patentgrep.com/patent/US12005156B2

## CPC

- A61L 27/26: Mixtures of macromolecular compounds
- A61F 2/30965: {Reinforcing the prosthesis by embedding particles or fibres during moulding or dipping}
- A61K 31/4375: the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
- A61L 27/20: Polysaccharides
- A61L 27/24: Collagen
- A61L 27/46: with phosphorus-containing inorganic fillers
- A61L 27/48: with macromolecular fillers
- A61L 27/54: Biologically active materials, e.g. therapeutic substances {(A61L27/227 takes precedence)}
- A61L 27/58: Materials at least partially resorbable by the body
- D01D 5/0038: {the fibre formed by solvent evaporation, i.e. dry electro-spinning}
- D01D 5/0084: {Coating by electro-spinning, i.e. the electro-spun fibres are not removed from the collecting device but remain integral with it, e.g. coating of prostheses}
- D01F 1/10: Other agents for modifying properties
- D01F 6/625: {derived from hydroxy-carboxylic acids, e.g. lactones}
- D04H 1/4282: Addition polymers
- D04H 1/435: Polyesters
- D04H 1/728: by electro-spinning {(electro-spinning methods and apparatus D01D5/0007)}
- D04H 3/007: Addition polymers
- D04H 3/011: Polyesters
- D04H 3/02: characterised by the method of forming fleeces or layers, e.g. reorientation of yarns or filaments
- D04H 3/16: with bonds between thermoplastic filaments produced in association with filament formation, e.g. immediately following extrusion
- D06M 15/03: Polysaccharides or derivatives thereof
- D06M 15/15: Proteins or derivatives thereof
- D06M 23/10: Processes in which the treating agent is dissolved or dispersed in organic solvents; Processes for the recovery of organic solvents thereof
- A61L 2300/208: Quaternary ammonium compounds
- A61L 2400/12: Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces
- A61L 2430/02: for reconstruction of bones; weight-bearing implants
- D06M 2101/18: Synthetic fibres consisting of macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds
- D06M 2101/32: Polyesters
- D10B 2321/12: polymers of cyclic compounds with one carbon-to-carbon double bond in the side chain
- D10B 2331/041: derived from hydroxy-carboxylic acids, e.g. lactones
- D10B 2509/00: Medical; Hygiene
- A61L: METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES (preservation of bodies or disinfecting characterised by the agents employed A01N; preserving, e.g. sterilising, food or foodstuffs A23; preparations for medical, dental or toiletry purposes A61K)
- A61F: FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS (dental prosthetics A61C)
- 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)
- D01D: MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
- D01F: CHEMICAL FEATURES IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS; APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OF CARBON FILAMENTS
- D04H: MAKING TEXTILE FABRICS, e.g. FROM FIBRES OR FILAMENTARY MATERIAL (weaving D03; knitting D04B; braiding D04C; net-making D04G; sewing D05B; tufting D05C; finishing non-woven fabrics D06); FABRICS MADE BY SUCH PROCESSES OR APPARATUS, e.g. FELTS, NON-WOVEN FABRICS; COTTON-WOOL; WADDING {; NON-WOVEN FABRICS FROM STAPLE FIBRES, FILAMENTS OR YARNS, BONDED WITH AT LEAST ONE WEB-LIKE MATERIAL DURING THEIR CONSOLIDATION}(non-woven fabrics having an intermediate or external layer of a different kind, e.g. of woven fabric, B32B)
- D06M: TREATMENT, NOT PROVIDED FOR ELSEWHERE IN CLASS D06, OF FIBRES, THREADS, YARNS, FABRICS, FEATHERS OR FIBROUS GOODS MADE FROM SUCH MATERIALS
- D10B: INDEXING SCHEME ASSOCIATED WITH SUBLASSES OF SECTION D, RELATING TO TEXTILES

## Abstract

The invention relates to bone repair and more specifically to a berberine/mineralized collagen-based composite membrane, a preparation method, and an application thereof. The composite membrane includes a berberine nanofiber membrane and a mineralized collagen membrane disposed on a unilateral surface of the berberine nanofiber membrane. The mineralized collagen with biomimetic mineralization capacity is combined with a Chinese materia medica monomer, berberine, the resulting bilayer composite membrane has a better effect on promoting osteogenesis In addition, a novel dosage form of berberine is constructed. An electrospinning method prepares a berberine nanofiber membrane. The berberine nanofibers are received by the mineralized collagen membrane, or after the berberine nanofiber membrane is obtained, a mineralized collagen membrane is prepared by applying on the surface of the berberine nanofiber membrane.

## Claims

### Claim 1

A preparation method of a berberine/mineralized collagen-based composite membrane comprising the following steps:
(1) mixing chitosan and mineralized collagen with a glacial acetic acid solution to obtain a resulting mineralized collagen suspension;
(2) mixing polycaprolactone, water-soluble compounds, and berberine with a solvent to obtain an electrospinning solution; and
(3) casting the resulting mineralized collagen suspension obtained in step (1) into a film to obtain a mineralized collagen membrane, and electrospinning the electrospinning solution obtained in step (2) and receiving resulting electrospun fibers on the mineralized collagen membrane to obtain the berberine/mineralized collagen-based composite membrane;
or electrospinning the electrospinning solution obtained in step (2) to obtain a berberine nanofiber membrane, coating the resulting mineralized collagen suspension obtained in step (1) on the berberine nanofiber membrane, and drying the coated berberine nanofiber membrane to obtain the berberine/mineralized collagen-based composite membrane;
wherein in the berberine/mineralized collagen-based composite membrane, the berberine nanofiber membrane comprises components of the following mass fractions: 20-65 wt % of polycaprolactone, 18-80 wt % of water-soluble compounds, and berberine≤0.1 wt % based on the mass of the berberine nanofiber membrane; and the mineralized collagen membrane comprises components of the following mass fractions: 15-90 wt % of chitosan, and 10-85 wt % of mineralized collagen based on the mass of the mineralized collagen membrane;
the mixing processes in step (2) are as below: berberine is dissolved in the solvent to get a berberine solution, then polycaprolactone and the water-soluble compounds are respectively dissolved in the berberine solution to get a polycaprolactone-berberine solution and a water-soluble compound-berberine solution; the polycaprolactone-berberine solution and the water-soluble compound-berberine solution are mixed to get the electrospinning solution; and
wherein the mass concentration of polycaprolactone in the polycaprolactone-berberine solution is 5-15%; the mass concentration of the water-soluble compounds in the water-soluble compound-berberine solution is 10-30%; the volume ratio of the polycaprolactone-berberine solution to the water-soluble compound-berberine solution is 7:(2-4); the concentration of berberine in the electrospinning solution is 5-50 μmol/L; the solvent is a mixed solvent of trichloromethane and methanol.

### Claim 2 (depends on 1)

The preparation method according to claim 1, wherein, the diameter of the fibers in the berberine nanofiber membrane is 700-800 nm.

### Claim 3 (depends on 1)

The preparation method according to claim 1, wherein, the thickness of the berberine nanofiber membrane is 0.1-0.4 mm, and the thickness of the mineralized collagen membrane is 0.1-0.4 mm.

### Claim 4 (depends on 1)

The preparation method according to claim 1, wherein, the chitosan has a molecular weight of 12-50 kDa.

### Claim 5 (depends on 1)

The preparation method according to claim 1, wherein, in the mineralized collagen suspension of step (1), the mass fraction of chitosan is 0.5-6%, and the mass fraction of the mineralized collagen is 0.1-2%.

### Claim 6 (depends on 1)

The preparation method according to claim 1, wherein, the method for casting into a film in step (3) is as below: the mineralized collagen suspension is poured into a mould and dried to get the mineralized collagen membrane; the drying temperature is 25-45° C., and the time is 2-5 h.

### Claim 7 (depends on 1)

The preparation method according to claim 1, wherein the volume ratio of trichloromethane to methanol in the mixed solvent is (2-4):1.

### Claim 8 (depends on 1)

The preparation method according to claim 1, wherein, in step (3), the parameters for electrospinning comprise: the liquid flow rate is 0.01-0.1 mm/min, the receiving distance is 10-15 cm, and the forward voltage is 10-15 kV.