Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/42—Phosphorus; Compounds thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; 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
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/02—Inorganic materials
  • A61L27/12—Phosphorus-containing materials, e.g. apatite
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; 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
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
  • A61L27/42—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having an inorganic matrix
  • A61L27/425—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having an inorganic matrix of phosphorus containing material, e.g. apatite

Definitions

• the invention pertains to biocompatible compositions containing ceramic particles, in particular hydroxyapatite, for soft and hard tissue augmentation, especially for bone regeneration and treatment of skin contour deficiencies, and for cosmetic use in plastic surgery, in particular for filling soft tissue voids or creating soft tissue augmentation.
• biomaterials Since long biocompatible materials have been applied in augmenting soft tissue in the practice of plastic and reconstructive surgery. These biomaterials are commonly delivered to the tissue site where augmentation is desired by means of an injectable composition that comprises the biomaterial and a biocompatible fluid, wherein the fluid acts as a lubricant to improve the delivery of the biomaterial suspension.
• WO-A-93/16657 teaches the use of injectable ceramic compositions comprising biocompatible ceramic materials such as calcium hydroxyapatite in a fluid carrier. These ceramics show excellent performance in repair and augmentation of soft and hard tissues. Further, hydroxyapatite has very low immunogenicity.
• the 50-250 ⁇ m sized ceramic particles are stabilized in a viscous or even gel-like organic polymer, such as polyethylene glycol, hyaluronic acid, poly(hydroxyethyl methacrylate), or in a collagen hydrogel.
• WO-A-93/15721 discloses a matrix of smooth, rounded, substantially spherical, finely divided particles of calcium hydroxyapatite in a biocompatible, resorbable lubricious gel carrier comprising a polysaccharide.
• the particles are typically in the range of 35-150 ⁇ m to minimize the possibility of particle migration by phagocytosis and to facilitate injectability.
• the carrier serves to further improve the delivery of the augmentation material by injection to the tissue site where augmentation is desired, and is typically formed from water, about 25 wt % glycerin and sodium carboxymethyl cellulose. It enables the ceramic particles to remain in suspension without settling for an indefinite period of time until used, more specifically at least about 6 months.
• U.S. Pat. No. 4,803,075 suggests the use of further biocompatible fluid lubricants and/or viscosity modifiers, such as glycogen, maltose and the like.
• the invention thus pertains to a biocompatible composition, suitable for use in soft or hard tissue augmentation, wherein the composition is an aqueous suspension containing a carrier fraction of ceramic particles of less than 15 ⁇ m and an augmentation fraction of ceramic particles of at least 20 ⁇ m.
• the ceramic particles of the two fractions together preferably make up for more than 95 wt %, more preferably more than 98 wt % of the total solids of the composition.
• the invention especially pertains to such a composition for medical use, as a therapeutic agent.
• particle sizes apply to the largest dimension of the particle, unless stated otherwise.
• the term “gel” or “suspension” is used to refer to the mix of carrier particles in water, while the term “composition” refers to the mixture of augmentation particles and the aforementioned gel or suspension. It is noted that the biocompatible composition in itself may also be characterized as a suspension. In the context of the invention, the different wording is merely intended to distinguish between the ready-to-use composition and its precursor.
• the ceramic particles preferably comprise calcium phosphate, calcium silicate, calcium carbonate or fluorides.
• the ceramic material is preferably a calcium phosphate, particularly comprising hydroxyapatite, also known as basic calcium phosphate, which is the natural mineral phase of teeth and bones.
• hydroxyapatite also known as basic calcium phosphate, which is the natural mineral phase of teeth and bones.
• Known hydroxyapatite derivates are included. Examples include, but are not limited to, tetracalcium phosphate, calcium pyrophosphate, tricalcium phosphate, octacalcium phosphate, calcium fluorapatite, calcium carbonate apatite, and combinations thereof.
• Other equivalent calcium-based compositions can also be used, such as calcium carbonate, and the like. These materials are commercially available, and a selection can be made from a number of mesh sized and porosities. The choice of material is regardless of the microstructure, protonation status of the phosphate, or extent of hydr
• the larger particles are considered as the “augmentation particles”, and will addressed as such from now on.
• These augmentation particles are suspended under aqueous conditions. It is found that such aqueous matrix comprising augmentation particles may be stabilized by a fraction of smaller particles of the same or another biocompatible ceramic material. Stabilization is required to homogenize the ceramic augmentation particles for an indefinite amount of time, at least sufficiently long to allow further processing and to inject the composition.
• the smaller ceramic particles take over the role of the lubricous gel carrier of non-ceramic materials presently applied in the art for stabilization, homogenization and lubrication purposes, and may thus beneficially replace the conventional foreign body carrier materials or lubricants.
• these smaller particles of biocompatible ceramic material are referred to as “carrier particles” in the context of the invention.
• carrier particles may be applied in compositions for either soft or hard tissue augmentation, which compositions mainly vary in the type, size and amount of augmentation particles present therein.
• the invention rests in the combination of these conventional augmentation materials with the carrier particles as characterized here below.
• the carrier particles are preferably larger than 100 nm. More preferably, these carrier particles have an average size larger than 1 ⁇ m. Preferably, the carrier particles have a size of less than 10 ⁇ m. Best results are obtained with carrier particles smaller than 5 ⁇ m.
• the carrier particles are preferably smaller than 1000 nm, more preferably 20-500 nm, in particular 25-300 nm.
• the carrier fraction preferably comprises hydroxyapatite (HA) and/or TCP.
• HA hydroxyapatite
• These carrier particles may be obtained from commercially available grades of ceramics, by conventional sieving, micronization or precipitation from calcium nitrate and ammonium phosphate.
• the precipitate may be spray dried and/or sintered (i.e. calcinated).
• the precipitate may be processed by centrifugation and optional sifting. Where the desired particles are obtained by sieving, this may be performed by “wet” or “dry” sieving.
• the particle size is predominantly determined by the selection of the starting material. Sieving and precipitation techniques are equally well applicable. Where a softer gel of augmentation particles is desired, it is preferred to use carrier particles as obtained by precipitation.
• the carrier particles contribute to the stability of the composition through their surface properties, it is preferred that more than 50%, preferably more than 75%, most preferably more than 90% of the total volume of particles in the carrier fraction is in singular or unagglomerated form. Agglomeration would only hamper the particles in achieving stability in the composition. It is thus preferred to subject a suitable source of carrier particles to a kind of “unagglomeration” treatment, for instance by subjecting the particles to a ball milling. This is in contrast to the augmentation particles, which could be formed by an agglomeration process.
• the stability of the suspension may be further improved selecting the material for the smaller particles on the basis of its interfacial properties, which may be fine-tuned by the preparation route. Since augmentation and carrier particles are present for different reasons, these materials do not necessarily have to be of the same origin. In fact, a selection of different materials may lead to better results, provided that the augmentation and carrier particles are chosen from the above-listed biocompatible materials.
• the augmentation particles are in essence indifferent from those traditionally applied in bone repair and in soft tissue augmentation.
• the preferred ceramics for use as augmentation particles comprises HA, fluorapatite, octacalcium phosphate and TCP.
• the augmentation particles comprise smooth and substantially rounded particles. These particles are preferably substantially spherical. “Substantially spherical” generally means a shape that is spheroidal. When viewing any cross-section of the particle, the difference between the average major diameter and the average minor diameter is less than 20%.
• the augmentation materials resemble perfect spheres, because of the optimum area-to-volume ratio and the positive effect on prevention of inflammations related therewith.
• the terms “rounded” or “smooth” as used herein refers to the fact even though the present particles are not perfect spheres, they do not have any sharp or angular edges, in order to improve injectability if so required. Surface milling and the like can improve surface smoothness.
• the augmentation particles must be sufficiently large so as to avoid rapid degradation. Resorbtion occurs where smaller particles on the order of 15 ⁇ m or less become engulfed by the cells and removed by the lymphatic system from the site where the augmentation material has been introduced into the tissues.
• the augmentation particles will dissolve over time, for HA typically at a rate of 15 ⁇ m/year.
• the resorbtion time of the injected mass depends on the actual particle size.
• the upper limit of the augmentation particles is determined by its use, being in soft or hard tissue augmentation.
• soft tissue augmentation purposes it is desired that the composition is injectable, meaning that the composition can easily be injected through a syringe intradermally or subcutaneously.
• the upper limit of the particle size will be dictated by the particular injection equipment employed. That is, the particles must be sufficiently small so as to avoid aggregation and clogging of the syringe when being injected.
• a typical range for injection is from about 20 to 100 ⁇ m, more preferably from 25-50 ⁇ m.
• a narrow or even equivalent particle size range of augmentation particles due to the fact that a distribution of such smooth and round particles reduces friction, and facilitates the ease of injecting the particles by needle from a syringe into the skin tissue at the desired augmentation site.
• This is in contrast to the use of the more porous, textured, irregularly shaped particles which tend to increase the frictional forces, and are much more difficult to deliver by injection.
• the size difference between the largest and the smallest (soft tissue) augmentation particle does not exceed about 35 ⁇ m.
• the augmentation particles are preferably much larger, typically between 100 ⁇ m and 4 mm, preferably between 1-1.5 mm.
• the surface porosity plays a more critical role. It is typically more than 30%, more preferably at least 50%, in order for the composition to provide a matrix for the ingrowth of new cartilage and bone.
• the augmentation particles and carrier particles are preferably present in the composition in a weight ratio of 0.5:1 to 15:1, more preferably up to 10:1. In case of soft tissue augmentation material, the weight ratio is even more preferably higher than 2:1, most preferably 4:1 to 9:1. These ceramic particles preferably form the only source of augmentation materials present in the composition.
• the composition should contain a sufficient volume of the larger ceramic particles (i.e. the augmentation particles) to provide an effective base for autogeneous tissue growth.
• a composition for use in soft tissue repair preferably 20-40 vol % of the total composition is formed from augmentation particles. In hard tissue repair, these numbers may be higher, since the augmentation particles are much larger, and may still be stabilized using corresponding amounts of water and carrier particles. There, it is preferred that the amount of augmentation particles is 10-60 vol % of the composition.
• the biocompatible composition contains little amount of ceramic particles having a size in between that of the augmentation particles and carrier particles. It is preferred that the composition is essentially free from biocompatible ceramic particles having a size outside the aforementioned ranges. However, from a practical perspective it should be understood that “essentially free from other biocompatible ceramic particles” means that small amounts of particles outside the desired ranges is allowed for in the composition, preferably less than 10 wt %, more preferably less than 5 wt % of the total amount of ceramic particles.
• the suspension is a multimodal distribution, preferably a bimodal distribution of ceramic particles, containing at least a mode of augmentation particles and a mode of carrier particles with one or more of the foregoing characteristics.
• the composition is free from any resorbable lubricants as described in the art, especially from polysaccharides such as carboxymethylcellulose or equivalents thereof, and glycerin.
• the composition is free from any foreign body material conventionally applied as augmentation material or lubricant or carrier thereof.
• all augmentation material present in the injectable biocompatible composition is a form of calcium phosphate.
• the composition may optionally comprise an amount of active ingredients.
• active ingredients can include substances that may provide therapeutic effects to the process of augmentation or biological or physiological responses to the dermal augmentation.
• An example of such therapeutic agent is an anti-inflammation agent that prevents or reduces the effect of inflammations associated with dermal augmentation, an anti-bacterial, anti-fungal or anti-histamine agent. It may also involve cell adhesion promoters, which enhance the adhesiveness of cells to the surface of the particles.
• Another suitable active ingredient is a local anaesthetic agent.
• the ceramic filler of the invention may be admixed with an osteoinductive factor (OFE), considered as one of the active ingredients optionally included in the composition.
• OFE useful in the composition of the invention is known to the person skilled in the art. The skilled person can easily recognize whether ingredients of the composition are included for augmentation or other purposes.
• the biocompatible composition of the invention contains 25-70 wt % water, 75-30 wt % of the biocompatible ceramic materials, and optionally up to 5 wt % of active ingredients. If active ingredients are present, the sum of water, carrier particles, augmentation particles and active ingredients is 100 wt %.
• the invention also pertains to the method of manufacturing the biocompatible composition of the invention.
• the composition is preferably prepared by mixing the augmentation particles and carrier particles and water at ambient conditions until all components are suspended. Therein, it is preferred that the carrier particles are suspended prior to or simultaneously with the augmentation particles.
• an aqueous suspension or gel of carrier particles is first prepared, containing 10-55 wt %, preferably 15-45 wt %, more preferably 20-35 wt % of carrier particles.
• the invention also pertains to an aqueous suspension or gel of carrier particles with the aforementioned characteristics, and the use thereof for stabilization of augmentation materials.
• the suspension may be characterized as being a thixotropic non-Newtonian liquid.
• a thixotropic non-Newtonian liquid In the literature, where for instance in U.S. Pat. No. 5,922,025 in relation to conventional glycerin-containing cellulose-polysaccharide gels containing augmentation material mention is made of a minimum gel viscosity of about 20,000 mPa ⁇ s. According to U.S. Pat. No. 5,922,025, at lower values the particles do not remain in suspension. However, with the carrier particles of the invention, it is possible to prepare a suspension having a viscosity as low as 5,000 mPa ⁇ s, and which is capable of stabilizing the biocompatible composition.
• the upper limit is not particularly limited, but may be adapted to the intended use. If the composition is to be injected for soft tissue repair, it is preferred that the gel viscosity is smaller than 30,000 mPa ⁇ s. For hard tissue repair there does not appear to be such restriction.
• the aqueous composition thus obtained may be sterilized by means known in the art, among which, favorably, gamma radiation.
• This adds an additional advantage to the composition of the invention over the aqueous gels of corresponding augmentation ceramic materials in a matrix containing polysaccharides and/or glycerine known in the art, which are said to be destroyed upon gamma sterilization.
• sterilization is no longer limited to autoclaving.
• the biocompatible composition may be used for regeneration of hard tissues, such as bone, cartilage, connective tissues and the like.
• the materials may even be formed into implants.
• the methods for utilizing the composition of the invention in the repair of bones, including surgical methods of implanting, are well understood in the art, and the compositions of the invention are useful in employing these standard means.
• the composition of the invention is applied in soft tissue augmentation.
• the present invention encompasses the use of the biocompatible compositions to treat skin deficiencies caused by diseases such as acne, cancer and lipodystrophy syndrome. Further, the invention encompasses the treatment of scars on or within the skin caused by accidents, wounds and injuries.
• the skin deficiencies may also be the result of the treatment of a disease.
• the dermal augmentation method of the invention is also suitable for the treatment of skin contour deficiencies, which are often caused by aging, environmental exposure, weight loss, child bearing, injury and surgery.
• Suitable for the treatment by the method of the present invention are contour deficiencies such as frown lines, worry lines, wrinkles, crow's feet, marionette lines, stretch marks, and internal and external scars resulted from injury, wound, bite, surgery, or accident.
• the invention works particularly well with contour deficiencies of such areas as cheeks, nose, forehead and neck.
• the biocompatible compositions may also be applied to augment internal tissues such as tissue defining sphincters in the treatment of incontinence, and for the treatment of unilateral vocal cord paralysis.
• the invention further pertains to a process of cosmetically improving the bodily appearance of a mammal, comprising introducing to the mammal's body subcutaneously or intradermally the composition of the invention in injectable form.
• the composition is preferably injected at one of the aforementioned places into the mammal's body.
• the mammal is preferably a human being.
• the invention also pertains to a kit for one of the aforementioned applications, where the augmentation particles, the carrier particles and other optional components are packaged in ready-to-use syringes, for instance those as described above.
• Calcium phosphate (amorphous hydroxyapatite) particles are obtained by precipitation from calcium nitrate and ammonium phosphate. The resulting particles were less than 1 ⁇ m in size. After cleaning, a gel-like suspension was obtained.
• the gel contained, prior to mixing with the augmentation material, 35 wt % carrier particles and 65 wt % water.
• the augmentation particles were produced by spray-drying a slurry of precipitated calcium phosphate, as described above; and then sintered and sieved to obtain particles of 25-45 ⁇ m.
• the gel contained 35 wt % carrier particles and 65 wt % water, the mix contained 29.4 wt % carrier particles and 54.5 wt % water and 16.1 wt % augmentation particles.
• the weight ratio of augmentation particles to carrier particles was 0.5:1.
• the biocompatible composition thus obtained contained 7.0 wt % carrier particles, 34.2 wt % water and 58.8 wt % hard tissue augmentation particles.
• the weight ratio of augmentation particles:carrier particles 8:1.
• the mixture contained 34 vol % of augmentation particles, in terms of the total volume of the composition.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Epidemiology (AREA)
• Inorganic Chemistry (AREA)
• Dermatology (AREA)
• Oral & Maxillofacial Surgery (AREA)
• Transplantation (AREA)
• Pharmacology & Pharmacy (AREA)
• Materials Engineering (AREA)
• Composite Materials (AREA)
• Engineering & Computer Science (AREA)
• Materials For Medical Uses (AREA)
• Medicinal Preparation (AREA)

Priority Applications (1)

Applications Claiming Priority (5)

Related Parent Applications (1)

Related Child Applications (1)

Publications (1)

Family

ID=38786980

Family Applications (3)

Family Applications After (2)

Country Status (3)

Cited By (3)

Families Citing this family (5)

Citations (6)

Family Cites Families (3)

• 2007
  • 2007-10-04 WO PCT/NL2007/050479 patent/WO2008041846A2/fr active Application Filing
  • 2007-10-04 EP EP07834617A patent/EP2068952A2/fr not_active Withdrawn
  • 2007-10-04 US US12/444,514 patent/US20100136117A1/en not_active Abandoned
• 2012
  • 2012-11-26 US US13/684,912 patent/US9233189B2/en active Active
• 2015
  • 2015-12-11 US US14/966,902 patent/US20160095880A1/en not_active Abandoned

Patent Citations (6)

Non-Patent Citations (2)

Also Published As

Similar Documents

Legal Events