United States Patent: 6,066,325
Inventors: Wallace; Donald G. (Menlo Park, CA); Reich; Cary J. (Los Gatos, CA); Shargill; Narinder S. (Dublin, CA); Vega; Felix (San Francisco, CA); Osawa; A. Edward (San Francisco, CA).Assignee: Fusion Medical Technologies, Inc. (Mountain View, CA).
Appl. No.: 32,370Filed: Feb. 27, 1998
Abstract
Cross-linked hydrogels comprise a variety of biologic and non-biologic polymers, such as proteins, polysaccharides, and synthetic polymers. Such hydrogels preferably have no free aqueous phase and may be applied to target sites in a patient's body by extruding the hydrogel through an orifice at the target site. Alternatively, the hydrogels may be mechanically disrupted and used in implantable articles, such as breast implants. When used in vivo, the compositions are useful for controlled release drug delivery, for inhibiting post-surgical spinal and other tissue adhesions, for filling tissue divots, tissue tracts, body cavities, surgical defects, and the like.
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 delivering drugs and other active agents, such as
biological macromolecules, polypeptides, oligopeptides, nucleic acids,
small molecule drugs, and the like. The compositions will comprise
biocompatible, cross-linked hydrogels, as described in more detail below,
and the drug or other biologically active agent will typically be
incorporated into the composition as an aqueous solution, suspension,
dispersion, or the like. The drugs may be incorporated into the
compositions prior to packaging, immediately prior to use, or even as the
compositions are being applied to the target site. After introduction to
the target site, the drug will usually be released over time as the
composition degrades. In some instances, however, the drug or other
biological agent may display activity while still incorporated or
entrapped within the hydrogel. For example, the compositions and methods
may find specific 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 have other uses as well, such as tissue
supplementation, 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 cellular or enzyme degradation
by a protective 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 also find use for inhibiting the formation of tissue
adhesions, such as spinal tissue adhesions, following surgery and
traumatic injury.
The compositions of the present invention comprise a biocompatible,
molecular cross-linked hydrogel. Usually the compositions will have
substantially no free aqueous phase as defined herein below. The hydrogel
is resorbable and fragmented, i.e. comprises small subunits having a size
and other physical properties which enhance the flowability of the
hydrogel (e.g. the ability to be extruded through a syringe) and the
ability of the hydrogel to otherwise be applied 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 fragmented 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, when packed into a
delivery site using a spatula, when sprayed onto the delivery site, or the
like. The threshold stresses are typically in the range from 3x104
Pa to 5x105 Pa. The compositions, however, will remain
generally immobile when subjected to stresses below the threshold level.
By "biocompatible," it is meant that the compositions will be
suitable for delivery to and implantation within a human patient. In
particular, the compositions will be non-toxic, non-inflammatory (or will
display a limited inflammatory effect which is not inconsistent with their
implantation), and be free from other adverse biological effects.
By "biodegradable," it is meant that the compositions will
degrade and breakdown into smaller molecular subunits that will be
resorbed and/or eliminated by the body over time, preferably within the
time limits set forth below.
By "substantially free of an aqueous phase" it is meant that the
compositions will be fully or partially hydrated, but will not be hydrated
above their capacity to absorb water. In particular, a test for
determining whether a composition has a free aqueous phase is set forth in
Example 8 below. Hydrogels which are substantially free of an aqueous
phase should release less than 10% by weight aqueous phase when subjected
to a 10 lb. force in the test, preferably releasing less than 5% by
weight, and more preferably less than 1% by weight, and more preferably
releasing no discernable aqueous phase and displaying no collapse.
The compositions may be dry, partially hydrated or fully hydrated
depending on the extent of hydration. The fully hydrated material will
hold from about 400% to about 5000% 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
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:
______________________________________
Particle/Subunit Size
Exemplary Range
Preferred Range
______________________________________
Dry Particle 0.01 mm-1.5 mm
0.05 mm-1 mm
Fully Hydrated
0.02 mm-3 mm
0.1 mm-1.5 mm
Hydrogel Subunit
______________________________________
Compositions of the present invention will usually be in the form of a dry powder, a partially hydrated hydrogel, or a fully hydrated hydrogel. 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 hydrogels 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 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 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 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 high, typically above 50% of the equilibrium hydration level, usually in the range from 70% 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 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 disruption of the hydrated, cross-linked hydrogels is generally simpler and involves fewer steps than does comminution of a dry polymer starting material. Thus, the disruption of hydrated hydrogels may be preferred when the ultimate hydrogel subunit size and/or size distribution is less critical.
In a first exemplary production process, a dry, non-cross-linked polymer starting material, e.g. dry gelatin powder, is mechanically disrupted by a conventional unit operation, such as homogenization, grinding, coacervation, milling, jet 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 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 nozzle, to form droplets which are released into a counter-current 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 is an alternative to mechanical disruption of the starting material. The spray drying operation will usually produce a non-cross-linked dry powder product which is spherical in shape with a generally uniform particle size. The particles may then be cross-linked, as described below.
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 cases, however, where more precise particle size distributions are required, the disrupted material can be further treated or selected to provide the desired particle size distribution, e.g. by sieving, aggregation, or the like. The mechanically disrupted polymeric starting material is then cross-linked as described in more detail below, and dried.
The dried material may be the desired final product, where it may be rehydrated and swollen immediately prior to use. Alternatively, the mechanically disrupted, cross-linked material may be rehydrated, and the rehydrated material packaged for storage and subsequent use. Particular methods for packaging and using these materials are described below.
Where the subunit size of the fragmented hydrogel is less important, the dried polymeric starting material may be hydrated, dissolved, or suspended in a suitable buffer and cross-linked prior to mechanical disruption. Mechanical disruption of the pre-formed hydrogel will typically be achieved by passing the hydrogel through an orifice, where the size of the orifice and force of extrusion together determine the particle size and particle size distribution. While this method is often operationally simpler than the mechanical disruption of dry polymeric particles prior to hydration and cross-linking, the ability to control the hydrogel particle size is much less precise.
In a particular aspect of the mechanical disruption of pre-formed hydrogels, the hydrogels may be packed in a syringe or other applicator prior to mechanical disruption. The materials will then be mechanically disrupted as they are applied through the syringe to the tissue target site, as discussed in more detail below. Alternatively, a non-disrupted, cross-linked polymeric material may be stored in a dry form prior to use. The dry material may then be loaded into a syringe or other suitable applicator, hydrated within the applicator, and mechanically disrupted as the material is delivered to the target site, again typically being through an orifice or small tubular lumen.
The polymer will be capable of being cross-linked and of being hydrated to form a hydrogel, as described in more detail below. Exemplary polymers include proteins selected from gelatin, collagen (e.g. soluble collagen), albumin, hemoglobin, fibrinogen, fibrin, fibronectin, elastin, keratin, laminin, casein and derivatives and combinations thereof. Alternatively, the polymer may comprise a polysaccharide, such as a glycosaminoglycan (e.g., hyaluronic acid or chondroitin sulfate), a starch derivative, a cellulose derivative, a hemicellulose derivative, xylan, agarose, alginate, chitosan, and combinations thereof. As a further alternative, the polymer may comprise a non-biologic hydrogel-forming polymer, such as polyacrylates, polymethacrylates, polyacrylamides, polyvinyl polymers, polylactide-glycolides, polycaprolactones, polyoxyethylenes, and derivatives and combinations thereof.
Cross-linking of the polymer may be achieved in any conventional manner. For example, in the case of proteins, cross-linking may be achieved using a suitable cross-linking agent, such as an aldehyde, sodium periodate, epoxy compounds, and the like. Alternatively, cross-linking may be induced by exposure to radiation, such as .gamma.-radiation or electron beam radiation. Polysaccharides and non-biologic polymers may also be cross-linked using suitable cross-linking agents and radiation. Additionally, non-biologic polymers may be synthesized as cross-linked polymers and copolymers. For example, reactions between mono- and poly-unsaturated monomers can result in synthetic polymers having controlled degrees of cross-linking. Typically, the polymer molecules will each have a molecular weight in the range from 20 kD to 200 kD, and will have at least one link to another polymer molecule in the network, often having from 1 to 5 links, where the actual level of cross-linking is selected in part to provide a desired rate of biodegradability in the ranges set forth below.
The extent of cross-linking of the polymer has an effect on several functional properties of the hydrogel including extrudability, adsorptiveness of surrounding biological fluids, cohesiveness, ability to fill space, swelling ability and ability to adhere to the tissue site. The extent of cross-linking of the polymeric hydrogel composition may be controlled by adjusting the concentration of cross-linking agent, controlling exposure to cross-linking radiation, changing the relative amounts of mono- and poly-unsaturated monomers, varying reaction conditions, and the like. Typically, the degree of cross-linking is controlled by adjusting the concentration of cross-linking agent.
Exposure to radiation, such as .gamma.-radiation, may also be carried out in order to sterilize the compositions before or after packaging. When the compositions are composed of radiation-sensitive materials, it will be necessary to protect the compositions from the undesirable effects of sterilizing radiation. For example, in some cases, it will be desirable to add a stabilizer, such as ascorbic acid, in order to inhibit degradation and/or further excessive cross-linking of the materials by free radical mechanisms.
The hydrogel compositions of the present invention will typically have a solids content in the range from 1% by weight to 70% by weight. Optionally, the compositions may comprise at least one plasticizer as described in more detail below. Suitable plasticizers include polyethylene glycols, sorbitol, glycerol, and the like.
The equilibrium swell of the cross-linked polymers of the present invention may range from 400% to 5000%, 400% to 3000%, 400% to 2000%, usually ranging from 400% to 1300%, preferably being from 500% to 1100%, depending on its intended use. Such equilibrium swell may be controlled by varying the degree of cross-linking, which in turn is achieved by varying the cross-linking conditions, such as the type of cross-linking method, duration of exposure of a cross-linking agent, concentration of a cross-linking agent, cross-linking temperature, and the like.
Gelatin-containing hydrogels having equilibrium swell values from about 400% to 1300% were prepared and are described in the Experimental section hereinafter. It was found that materials having differing equilibrium swell values perform differently in different applications. For example, the ability to inhibit bleeding in a liver divot model was most readily achieved with cross-linked gelatin materials having a swell in the range from 600% to 950%, often from 700% to 950%. For a femoral artery plug, lower equilibrium swell values in the range from 500% to 600% were more successful. Thus, the ability to control cross-linking and equilibrium swell allows the compositions of the present invention to be optimized for a variety of uses.
In addition to equilibrium swell, it is also important to control the hydration of the material immediately prior to delivery to a target site. Hydration is defined as the percentage of water contained by the hydrogel compared to that contained by the hydrogel when its fully saturated, that is, at its equilibrium swell. A material with 0% hydration will be non-swollen. A material with 100% hydration will be at its equilibrium water content and fully swollen. Hydrations between 0% and 100% will correspond to swelling between the minimum and maximum amounts. As a practical matter, many dry, non-swollen materials according to the present invention will have some residual moisture content, usually below 20% by weight, more usually from 8% to 15% by weight. When the term "dry" is used herein, it will specify materials having a low moisture content, usually below 20%, often below 10%, and frequently below 5% by weight, where the individual particles are free flowing and generally non-swollen.
Hydration can be adjusted very simply by controlling the amount of aqueous buffer added to a dry or partially hydrated cross-linked material prior to use. Usually, at a minimum, it will be desirable to introduce sufficient aqueous buffer to permit extrusion through a syringe or other delivery device. In other cases, however, it may be desirable to utilize a spatula or other applicator for delivering less fluid materials. The intended use will also help determine the desired degree of hydration. In cases where it is desired to fill or seal a moist cavity, it is generally desirable to employ a partially hydrated hydrogel which can swell and fill the cavity by absorbing moisture from the target site. Conversely, fully or substantially fully hydrated hydrogels are preferred for application in the brain, near the spine, and to target sites near nerves and other sensitive body structures which could be damaged by post-placement swelling. It would also be possible to prepare the hydrogel compositions of the present invention with excess buffer, resulting in a two-phase composition having a fully hydrated hydrogel and a free buffer phase.
A preferred hydrogel material according to the present invention is a gelatin which has been cross-linked to achieve from 600% to 950%, usually 700% to 950% swell at equilibrium hydration. The material will be disrupted to have a hydrogel particle size in the range from 0.01 mm to 1.75 mm, preferably 0.05 mm to 1.0 mm, often 0.05 mm to 0.75 mm, and frequently between 0.05 mm and 0.5 mm, and will preferably be hydrated at a level sufficient to achieve 70% to 100% of the equilibrium swell prior to application to the site.
In some cases, the hydrogel compositions of the present invention may contain a combination of two or more different materials, e.g combinations of proteins and polysaccharides and/or non-biologic polymers, as well as combinations of two or more individual materials from each of the polymer types, e.g. two or more proteins, polysaccharides, etc.
The polymeric compositions of the present invention may also comprise combinations of the disrupted, cross-linked polymer hydrogels described above and non-cross-linked polymeric materials. The disrupted, cross-linked polymeric hydrogels consist of a plurality of subunits having a size determined by preparation method. The size is selected to be useful for packing a confined volume, having both the flowability and the rate of biodegradability described in the Experimental section below. The discrete nature of the cross-linked subunits, however, will leave void areas which may be filled by combination with a non-cross-linked polymeric material. The non-cross-linked polymeric or other filler material may comprise any of the polymeric materials listed above, and may optionally but not necessarily be the same polymeric material which has been cross-linked to form the cross-linked mechanically disrupted hydrogel. The relative amounts of cross-linked polymer and non-cross-linked polymer may vary, typically having a weight ratio in the range from 20:1 to 1:1 (cross-linked polymer:non-cross-linked polymer), usually in the range from 10:1 to 2:1, preferably from 5:1 to 2:1.
The hydrogels of the present application may be applied using a syringe, a spatula, a brush, a spray, manually by pressure, or by any other conventional technique. Usually, the hydrogels will be applied using a syringe or similar applicator capable of extruding the hydrogel through an orifice, aperture, needle, tube, or other passage to form a bead, layer, or similar portion of material. Mechanical disruption of the hydrogels can occur as the hydrogel is extruded through an orifice in the syringe or other applicator, typically having a size in the range from 0.01 mm to 5.0 mm, preferably 0.5 mm to 2.5 mm. Preferably, however, the polymeric hydrogel will be initially prepared from a powder having a desired particle size (which upon hydration yields hydrogel subunits of the requisite size) or will be partially or entirely mechanically disrupted to the requisite size prior to a final extrusion or other application step.
The compositions may be applied at varying degrees of hydration, usually but not necessarily being at least partially hydrated. If applied in a non-hydrated form, the compositions will swell to their full equilibrium swell value, i.e. from about 400% to about 5000% as set forth above. When applied at their full hydration, the compositions will display substantially equilibrium hydration and little or no swelling when applied to tissue. Swelling of the non-hydrated and partially hydrated compositions results from absorption of moisture from the tissue and surroundings to which the composition is being applied.
The present invention still further provides kits comprising any of the hydrated or non-hydrated hydrogel materials described above in combination with written instructions for use (IFU) which set forth any of the methods described above for applying the hydrogel onto a target site on tissue. The composition and written instructions will be included together in a conventional container, such as a box, jar, pouch, tray, or the like. The written instructions may be printed on a separate sheet of paper or other material and packaged on or within the container or may be printed on the container itself. Usually, the composition(s) will be provided in a separate sterile bottle, jar, vial, or the like. When the hydrogel material is non-hydrated, the kit may optionally include a separate container with a suitable aqueous buffer for hydration. Other system components such as the applicator, e.g. syringe, may also be provided.
Claim 1 of 8 Claims
1. A fragmented biocompatible hydrogel which is at least
partially hydrated and is substantially free from an aqueous phase,
wherein said hydrogel comprises gelatin and will absorb water when
delivered to a moist tissue target site and, wherein the gel has a subunit
size in the range from 0.01 mm to 5 mm when fully hydrated and an
equilibrium swell from 400% to 5000%, said hydrogel being present in an
applicator.
____________________________________________
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