NZ201067A

NZ201067A - Collagen implant containing pharmacologically active material

Info

Publication number: NZ201067A
Application number: NZ201067A
Authority: NZ
Inventors: W Steffan; K H Sorg; A Stemberger
Original assignee: Schering Corp
Priority date: 1981-06-25
Filing date: 1982-06-24
Publication date: 1985-05-31
Also published as: ATE15763T1; JPH0118744B2; DE3266525D1; AU555952B2; JPS584551A; ZA824517B; AU8517782A; MX9203310A; EP0069260A3; DE3124981A1; IE53579B1; CA1183776A; IE821514L; EP0069260A2; EP0069260B1

Abstract

1. Collagen insert containing an active ingredient for introduction into bones or soft parts, characterized in that it is prepared by adding to a solution of high-purity native collagen, wherein the collagen has a factor of nitrogen to hydroxyproline =< 3 to 5, a solution or suspension of said active ingredient and then by drying with hot air or by freeze-drying a sheet is produced in the form of a fascia and finally it is optionally wound to form a rod.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £01 067 20 1067 lt fcwi-izi DaHs)' 2^-- L~s>) | ' Complete Specification Filed:-^4 Class: . ./^ j ^ Jc>o Publication Date: j?.l MAYjggg r?- JowmaJ, Wo: .'PrT7. I Ni No.: Date: NEW ZEALAND PATENTS ACT, 1953 COMPLETE SPECIFICATION "COLLAGEN IMPLANT CONTAINING ACTIVE INGREDIENT(S) FOR IMPLANTATION IN BONES OR SOFT TISSUES AND PROCESS FOR ITS MANUFACTURE" I3i£We, SCHERING CORPORATION, a corporation organized under and by virtue of the laws of -Hie State of New Jersey, United States of America, of 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States of America, hereby declare the invention for which lc^ we pray that a patent may be granted to and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 - (followed by page la) 201067 - la - Collagen Implant Containing Active Ingredient(s) for Implantation in Bones or Soft Tissues and Process for its Manufacture The invention concerns an implant resorbable in 5 the body and containing active ingredients, for implantation in bones and soft tissues. It especially relates to a collagen implant in the form of a sheet containing pharmacologically active ingredient(s), which optionally can be rolled into a rod and which 10 after implantation in the bone or tissue gradually releases the ingredient(s). It is known that collagen can be used as material which is bioresorbable in the body, for filling defects in bones or in soft tissues. 15 The use of polyhydroxy acetic acid ester for the manufacture of antibiotic-containing resorbable surgical materials, e.g. tubes, is known. A combination of an active ingredient with a polylactide or of a copolymer of lactide and glycolide units is 20 also known. The above-mentioned materials are synthetic polymers or copolymers which are decomposed in the body. Such polymers and copolymers have increasingly gained in significance because as fully synthetic 25 products they have readily reproducible properties and can be prepared in high purity. Materials of the above-mentioned polymers and copolymers are also used as synthetic resorbable suture materials. For many years collagen has been known as a 30 resorbable material and has been used hemostatically, <?• especially during and after surgical operations or "t^y fill body cavities or to cover wounds. There have , 20!067 - 2 - / always been certain problems concerning the degree of purity of collagen, since it is extracted from natural products, and is difficult to produce in high purity. However, collagen can be made with a high degree of 5 purity, so that complications can be avoided when using it for surgical purposes. A shaped mass resorbable in the body and based on collagen is also known. This shaped mass contains, in addition to denatured collagen, a bioresorbable binding 10 agent as well as optionally an active ingredient. The above-mentioned polymers and copolymers of glycolic acid or of lactide and glycolide are especially suitable as the bioresorbable binding agents. It is the object of this invention to provide a 15 bioresorbable implant containing a pharmacologically active ingredient for implantation in bones or soft tissues. This object has been attained by providing a very pure native collagen containing a pharmacologically 20 active ingredient. The invention therefore provides a collagen implant containing pharmacologically active ingredient(s) for implantation in bones or soft tissues, consisting of highly pure native collagen and having a factor nitrogen: hydroxyprol ine _< 3 to 5 and 25 charged with a pharmacologically active ingredient. The collagen implant can be in the form of a sheet or rod, the rod being made by rolling the collagen sheet. (By the term "native collagen" is meant collagen which is purified but not changed in its 30 structure.) The rod-shaped collagen product has about the same thickness as a pencil. It can be conveniently made by adding a solution of the active ingredient to a collagen solution; after • - 3 - 201 067 j drying; e.g. with hot air or by lyophilization, the collagen is^ first prepared in sheet form (as a so-called fascia) ." Also the reverse route, depending on the stability of the active ingredient, can be undertaken, by first preparing 5 the collagen fascia and then charging it with the active ingredient. This can be done e.g. by spraying an aqueous solution of an active ingredient, e.g. an antibiotic in the form of a salt on the collagen sheet and allowing it to dry there. Equally it is possible to apply the antibio-10 tic or another pharmacologically effective compound, by painting, rolling, dipping or sprinkling with an active ingredient in powder form or in a similar manner. The so obtained collagen sheet charged with the active ingredient can then be rolled into a rod-shaped product of about pencil 15 thickness. In this form it can be cut into any desired length depending on the desired dose and can be packed to remain sterile until used. Especially suitable active ingredients in combination with ■ collagen are aminoglycoside antibiotics, such as gentamycin. In salt form, e.g. as sulfate, gentamycin is , i TO- water-soluble and can be added to the collagen in a wide 2 i range from about 1 to about 100 mg/cm fascia or it can be sprayed on. The collagen sheet (collagen fascia) containing the gentamycin can then be rolled and dried and thereafter it maintains its rod-shape. i •26- Other active ingredients such as sulfonamides, antiseptics, or corticosteroids can be added instead of or in addition to the antibiotic. •«- The collagen used has a purity expressed by the factor nitrogen: hydroxy pro line <3 to 5. Such a collagen can be pre- -3©- pared in the manner described in the example. 1 ( Using the rod-shaped collagen charged with an active in- • " ■ ■ . 4" 1 . ' > . 4 - 20106 - 4 - gredient of the invention is of special advantage in that the active ingredient adheres very well to the collagen and optionally can even be bonded to it. To the extent that the collagen decomposes over a period of time, the active 5 ingredient is released/ so that there is a sustained release. A further advantage is that the carrier matrix collagen serves as a guide for proliferating connective tissue cells and thus promotes the healing of the wound in a known manner. 10 Example The following highly pure native collagen is prepared as follows: Fresh beef tendons freed from all pigment layers and residues of muscle were homogenised and an amount correspon-15 ding to 100 g dry weight was extracted with 3 liters 0.05 M citrate buffer (pH 3.7) for 24 hours and then dialysed for 12 hours against 1% acetic acid. The tissue, suspended in 3 liters 1% acetic acid, was incubated with constant stirring for 48 hours at 15°C with pepsin in a ratio of collagen 20 to pepsin of 50 : 1. The preparation was diluted with 1% acetic acid to 5 liters and then freed from undissolved tendon fragments by centri-fugation. The viscous collagen solution was dialysed against alkalised 25 tap water (pH 8.0) and was then vigorously centrifuged. The residue was again dissolved in 5 liters 1% acetic acid and dialysed. This process was repeated until the factor nitrogen :hydroxy-proline was J^.3. After the last dialysis a 1.5% collagen solution in 0.05% acetic acid was prepared. </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 20to - 5 - Preparation of the Collagen Implant containing Active Ingredient 10 ml of the 1.5% collagen solution obtained as above are placed in a dish of 10 x 10 cm. 100 mg gentamycin (in the 5 form of its sulfate) were added thereto. The solution was then lyophilized in the dish to yield a sponge-like mass having the shape of the dish. This sponge was then pressed into a fascia or sheet and optionally rolled into a rod-shaped product of pencil thickness. 10 The gentamycin-containing implant obtained in this way was sterile-packed and sterilised with ethylene oxide in known manner.. Use If the above-mentioned collagen implant containing 100 mg 15 gentamycin is introduced into the tibia, it is completely resorbed there within 3 weeks. During this time the gentamycin is released. 201067 - 6 - What we claim is:

1. Collagen implant containing pharmacologically active ingredient(s) for implantation in bones or soft tissues, consisting of highly pure native collagen 5 having a factor nitrogen:hydroxyproline <_ 3 to 5 and charged with a pharmacologically active ingredient.

2. Collagen implant according to claim 1 in sheet form.

3. Collagen implant according to claim 1 in the form 10 of a sheet rolled into a rod-shaped product.

4. Collagen implant according to any one of claims 1 to 3, wherein the active ingredient is an antibiotic.

5. Collagen implant according to claim 4 wherein the antibiotic is gentamycin. 15

6. Collagen implant containing pharmacologically active ingredient(s) according to claim 1 or 2 prepared, by admixing the active ingredient(s) in a suitable vehicle with a collagen solution and processing after drying into a sheet and then if desired rolling the 20 sheet into a rod.

7. Process for the preparation of a collagen implant containing pharmacologically active ingredient(s) according to claim 1, characterized in that highly pure native collagen having a factor nitrogen:hydroxyproline 25 <_ 3 to 5 is charged with pharmacologically active ingredient(s), processed into a sheet and optionally ' 1/'^ 201067 - 7 - rolled into a rod.

8. An implant as claimed in any one of claims 1 to 6 substantially as hereinabove described with reference to any Example thereof. 5

9. A process as claimed in claim 7 when performed substantially as herein described. By His/Thai r authorised A. J. PARK & SON ftr Xfc>c/. </div>