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COMPOSITIONS AND METHODS FOR
The present application is a continuation-in-part of pro- 5 vision application Ser. No. 60/050,437, filed on Jun. 18, 1997, and is a continuation-in-part of application Ser. No. 08/704,852, filed on Aug. 27, 1996, abandoned. The full disclosures of both of these applications are incorporated herein by reference. 10
BACKGROUND OF THE INVENTION 1. Field of the Invention
The present invention relates generally to cross-linked polymeric compositions and to the use of such compositions for inhibiting tissue adhesion and other purposes.
Tissue adhesions occur frequently following surgery and may contribute to or cause compromised surgical results and post-surgical complications. Tissue adhesions may result from unwanted or excessive scar tissue and occur in various 2Q body regions including pelvic, abdominal, spinal, tendon, ophthalmic, urinary, thoracic and cardiovascular tissues and are formed when normal tissue bonds to the surfaces of internal organs which have been traumatized or damaged during surgery. Such adhesions may join organs or other 2J body tissues that normally are separate. Treating adhesions may necessitate additional surgery with additional costs, danger and/or discomfort to the patient.
Of particular pertinence to the present application, tissue adhesions often occur after spinal surgery as the result of 30 scar tissue formation between the spinal cord nerves, and adjacent underlying tissues. Such scar tissue formation can compress the nerve roots, producing neural complications such as persistent low back pain and sciatica. At present, peridural scar tissue must be treated with additional surgery. 35
Numerous procedures and materials have been proposed to minimize or eliminate post-surgical adhesions. Such procedures include introducing barrier materials such as metals, polymers, and natural materials over the target site. A woven material of regenerated cellulose is currently 40 marketed for this purpose by Johnson & Johnson under the trademark Interceed®. This product, however, does not conform well to the underlying tissue. Other polymeric materials that have been tried for this purpose include nylon, cellophane, PTFE, polyethylene, siloxane, elastomers and 45 polylactic acid copolymer films. Many of these materials are not biodegradable and therefore, remain in the body with unpredictable and potentially undesirable consequences.
The reduction and elimination of post-surgical spinal adhesions has been particularly problematic. A variety of 50 permanently implanted devices have been proposed, such as those described in U.S. Pat. Nos. 5,437,672 and 4,013,078. The use of permanent implants, however, is undesirable. The use of resorbable barriers and films has also been proposed. Placement of such barriers and films, however, has also been 55 problematic. The regions between adjacent vertebrae are difficult to access, and it is very difficult to properly place and immobilize barriers and films. The use of non-solid anti-adhesive materials is also problematic since such materials must be sufficiently fluid to enter and conform to the 60 regions being treated, while being sufficiently viscous and persistent so that they remain in the space until the tissue is healed. These objectives must further be balanced with the requirements of biocompatibility and resorbability of the anti-adhesive compositions. 65
For these reasons, it would be desirable to provide improved compositions, methods, and articles for inhibiting
the formation of tissue adhesions following surgery and other trauma. In particular, it would be desirable to provide compositions and methods for introducing such compositions in vivo for the prevention and inhibition of peridural adhesions following laminectomies or other surgical procedures on the spinal column. It would be further desirable if such compositions were useful for the prevention or inhibition of adhesions elsewhere in the body and for other in vivo purposes, such as a filler for tissue voids such as divots resulting from tissue biopsies or other blunt tissue trauma, the filling of implants, such as breast implants, the sealing and/or hemostasis of percutaneous penetrations, and the filling and supplementation of other constrained regions within a patient's body. Moreover, the compositions and methods of the present invention should be adaptable for delivering drugs and other biologically active substances to tissue surfaces adjacent to regions where the compositions have been implanted. At least some of these objectives will be met by the embodiments of the invention of the present application described hereinafter.
2. Description of the Background Art
Barrier films and materials used for preventing or inhibiting spinal and other adhesions are described in U.S. Pat. Nos. 5,350,573, 5,140,016; 5,135,751; 5,134,229; 5,126, 141;, 5,080,893; 5,017,229; 5,007,916; PCT publications WO 92/21354; WO 95/15747; WO 86/00912; and Boyers et al. (1988) Fert. Ster. 49: 1066-1070. U.S. Pat. Nos. 5,437, 672 and 4,013,078 each describe intervertebral protective devices which remain as permanent implants along the patient's spinal cord.
Collagen and other polymeric plugs intended for sealing percutaneous penetrations, such as tissue tracts created by accessing the femoral artery, are described in a number of patents, including U.S. Pat. Nos. 5,540,715, 5,531,759, 5,478,352; 5,275,616; 5,192,300; 5,108,421; and 5,061,274.
Collagen-containing compositions which have been mechanically disrupted to alter their physical properties are described in U.S. Pat. Nos. 5,428,024; 5,352,715; and 5,204, 382. These patents generally relate to fibrillar and insoluble collagens. An injectable collagen composition is described in U.S. Pat. No. 4,803,075. An injectable bone/cartilage composition is described in U.S. Pat. No. 5,516,532. A collagen-based delivery matrix comprising dry particles in the size range from 5 fim to 850 fim which may be suspended in water and which has a particular surface charge density is described in WO 96/39159. A collagen preparation having a particle size from 1 fim to 50 fim useful as an aerosol spray to form a wound dressing is described in U.S. Pat. No. 5,196,185.
A polymeric, non-erodible hydrogel that may be crosslinked and injected via a syringe is described in WO 96/06883. A polyoxyalkylene polymer for inhibiting adhesion is described in U.S. Pat. No. 5,126,141.
The following pending applications, assigned to the assignee of the present application, contain related subject matter: U.S. Ser. No. 60/050,437, filed on Jun. 18, 1997; U.S. Ser. No. 08/704,852, filed on Aug. 27, 1996; U.S. Ser. No. 08/673,710, filed Jun. 19, 1996; U.S. Ser. No. 60/011, 898, filed Feb. 20, 1996; U.S. Ser. No. 60/006,321, filed on Nov. 7, 1996; U.S. Ser. No. 60/006,322, filed on Nov. 7, 1996; U.S. Ser. No. 60/006,324, filed on Nov. 7, 1996; and U.S. Ser. No. 08/481,712, filed on Jun. 7, 1995. The full disclosures of each of these applications is incorporated herein by reference.
SUMMARY OF THE INVENTION
The present invention provides improved biocompatible polymeric compositions and methods for applying such
compositions at target sites in a patient's body. The methods and compositions will be particularly useful for preventing or inhibiting the formation of tissue adhesions, such as spinal tissue adhesions, following surgery and traumatic injury. In addition, the compositions and methods may also find use in stopping or inhibiting bleeding (hemostasis), particularly when combined with a suitable hemostatic agent, such as thrombin, fibrinogen, clotting factors, and the like. The compositions will be further useful for supplementing tissues, particularly for filling soft and hard tissue regions, including divots, tracts, body cavities, etc., present in muscle, skin, epithelial tissue, connective or supporting tissue, nerve tissue, ophthalmic and other sense organ tissue, vascular and cardiac tissue, gastrointestinal organs and tissue, pleura and other pulmonary tissue, kidney, endocrine glands, male and female reproductive organs, adipose tissue, liver, pancreas, lymph, cartilage, bone, oral tissue, and mucosal tissue. The compositions of the present invention will be still further useful for filling soft implantable devices, such as breast implants, where the material will be protected from degradation by a cellular/enzyme-impermeable barrier or cover. The compositions will additionally be useful in other procedures where it is desirable to fill a confined space with a biocompatible and resorbable polymeric material. Additionally, the compositions may be combined with drugs and other biologically active agents, where the drugs may be released at the target site over time.
The compositions of the present invention comprise a molecular, cross-linked hydrogel which is resorbable and comprises small subunits having a size and other physical properties which enhance the flowability of the gel (e.g. the ability to be extruded through a syringe) and the ability of the gel to flow onto and conform to sites on or in tissue, including tissue surfaces and defined cavities, e.g. intravertebral spaces, tissue divots, holes, pockets, and the like. In particular, the subunits are sized to permit them to flow when the compositions are subjected to stresses above a threshold level, for example when extruded through an orifice or cannula or when packed into a delivery site using a spatula, or the like. The threshold stresses are typically in the range from 3xl04 Pa to 5xl05 Pa. The compositions, however, will remain generally immobile when subjected to stresses below the threshold level.
The compositions may be dry, partially hydrated or fully hydrated and will display a degree of swelling from 0% to 100%, depending on the extent of hydration. The fully hydrated material will absorb from about 400% to about 1300% water or aqueous buffer by weight, corresponding to a nominal increase in diameter or width of an individual particle of subunit in the range from approximately 50% to approximately 500%, usually from approximately 50% to approximately 250%. Thus, the size of particles in the dry powder starting material (prior to hydration) will be determine the partially or fully hydrated size of the subunit (depending on the factors described below). Exemplary and preferred size ranges for the dry particles and fully hydrated subunits are as follows:
Exemplary Range Preferred Range
Dry Particle 0.01 mm-1.5 mm 0.05 mm-1 mm
Fully Hydrated 0.05 mm-3 mm 0.25 mm-1.5 mm
Compositions of the present invention will usually be in the form of a dry powder, a partially hydrated gel, or a fully
hydrated gel. The dry powder (having a moisture content below 20% by weight) will be useful as a starting material for preparation of the hydrogels, as described below. The partially hydrated gels, typically having from 50% to 80%
5 hydration, are useful for applications where it is desired that the material further swell upon application to a moist target site, e.g. a tissue divot. The fully hydrated forms will be useful for applications where in situ swelling is not desired, such as in the spinal column and other areas where nerves
10 and other sensitive structures are present.
The dimensions of the subunits may be achieved in a variety of ways. For example, a cross-linked hydrogel having dimensions larger than the target range (as defined below) may be mechanically disrupted at a variety of points
15 during the production process. In particular, the composition may be disrupted (1) before or after cross-linking of a polymer starting material and (2) before or after hydration of the cross-linked or non-cross-linked polymer starting material, e.g. as a fully or partially hydrated material or as
20 a dry particulate powder. The term "dry" will mean that the moisture content is sufficiently low, typically below 20% by weight water, so that the powder will be free-flowing and that the individual particles will not aggregate. The term "hydrated" will mean that the moisture content is sufficiently
25 high, typically above 50% of the equilibrium hydration level, usually in the range from 80% to 95% of the equilibrium hydration level, so that the material will act as a hydrogel.
Mechanical disruption of the polymer material in the dry 30 state is preferred in cases where it is desired to control the particle size and/or particle size distribution. It is easier to control comminution of the dry particles than the hydrated hydrogel materials, and the size of the resulting reduced particles is thus easier to adjust. Conversely, mechanical 35 disruption of the hydrated, cross-linked hydrogels is generally simpler and involves fewer steps than does commination of a dry polymer starting material. Thus, the disruption of hydrated gels may be preferred when the ultimate gel subunit size and/or size distribution is not critical.
In a first exemplary production process, a dry, non-crosslinked polymer starting material, e.g. dry gelatin powder, is mechanically disrupted by a conventional unit operation, such as homogenization, grinding, coacervation, milling, jet
45 milling, and the like. The powder will be disrupted sufficiently to achieve dry particle sizes which produce hydrogel subunit sizes in the desired ranges when the product is partially or fully hydrated. The relationship between the dry particle size and the fully hydrated subunit size will depend
5Q on the swellability of the polymeric material, as defined further below.
Alternatively, a particulate polymeric starting material may be formed by spray drying. Spray drying processes rely on flowing a solution through a small orifice, such as a
55 nozzle, to form droplets which are released into a countercurrent or co-current gas stream, typically a heated gas stream. The gas evaporates solvent from the liquid starting material, which may be a solution, dispersion, or the like. Use of spray drying to form a dry powder starting material
60 is an alternative to mechanical disruption of the starting material. The spray drying operation will usually produce a non-cross-linked dry powder product with a highly uniform particle size. The particles may then be cross-linked, as described below.
65 In many instances, the mechanical disruption operation can be controlled sufficiently to obtain both the particle size and particle size distribution within a desired range. In other