WO2008066382A1 - Carboxymethyl cellulose-stabilised tissue filler and its preparation and use - Google Patents

Carboxymethyl cellulose-stabilised tissue filler and its preparation and use Download PDF

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WO2008066382A1
WO2008066382A1 PCT/NL2007/050605 NL2007050605W WO2008066382A1 WO 2008066382 A1 WO2008066382 A1 WO 2008066382A1 NL 2007050605 W NL2007050605 W NL 2007050605W WO 2008066382 A1 WO2008066382 A1 WO 2008066382A1
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cmc
tissue filler
tissue
suspension according
augmentation
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PCT/NL2007/050605
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French (fr)
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Klaas De Groot
Nol Van De Mortel
Nienke Beuling
Mariska Bezemer
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Cam Aesthetics B.V. I.O.
Cam Implants B.V.
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58Materials at least partially resorbable by the body
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/40Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L27/446Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with other specific inorganic fillers other than those covered by A61L27/443 or A61L27/46
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/40Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L27/46Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with phosphorus-containing inorganic fillers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/40Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L27/48Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with macromolecular fillers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52Hydrogels or hydrocolloids

Abstract

The invention pertains to a tissue filler suspension containing tissue filler material, wherein the suspension further contains carboxymethyl cellulose (CMC) and is free from glycerine and surfactant, preferably free from any foreign body materials other than said CMC. The suspension finds use in soft, hard and connective tissue augmentation; for that purpose ceramic particles, e.g. comprising calcium phosphate, and/or biodegradable polymers such as polylactic acid or PEG-BPT copolymer, may be applied. The CMC is characterized in that a 1.0 wt% concentration thereof in water would exhibit a viscosity of at least 9,000 mPas as determined by a Brookfield, LVT, 30 rpm, spindle 4, at a temperature of 25 °C. A suitable CMC is that described in WO- A-99/20657.

Description

CARBOXYMETHYL CELLULOSE-STABILISED TISSUE FILLER AND ITS PREPARATION AND USE

FIELD OF THE INVENTION The invention pertains to a carboxymethyl cellulose-stabilised tissue filler composition containing tissue filler material. The invention also pertains to the preparation of such composition, and to the use thereof in soft and hard tissue augmentation, especially for bone regeneration and treatment of skin contour deficiencies, both therapeutically as well as cosmetically in plastic surgery, especially in particular for filling tissue voids or creating tissue augmentation. In addition, the invention pertains to the use of the above composition in tissue regeneration, especially soft and connective tissue regeneration.

BACKGROUND OF THE INVENTION

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 degradable fluid acts as a lubricant to improve the delivery of the biomaterial suspension. Since the mid-eighties polymethylmethacrylate (PMMA) has been studied as a soft tissue augmentation device, in addition to the still popular collagen. The permanent character of PMMA and many other fillers such as silicones would make repetitive corrections unnecessary. However, it is discovered recently that the injection of PMMA microspheres causes all kinds of complications in time, to a large extent related to the non-biodegradable properties. Moreover, it is now believed that the permanent impact of filler materials in tissue is undesired, since the tissue itself is subject to ageing (see e.g. E. Haneke, ""Skin rejuvenation without a scalpel. I. Fillers", J Cosmetic Dermatology; 5: 157 - 167 (2005); K. De Boulle, "Management of complications after implantation of fillers", J Cosmetic Dermatology; 3: 2 - 15 (2004). WO-A-93/15721 teaches the use of injectable ceramic compositions comprising biocompatible ceramic materials such as calcium hydroxyapatite. These ceramics show excellent performance in repair and augmentation of soft tissues. Further, hydroxyapatite has very low immunogenicity. The filler material is suspended in a biocompatible, resorbable lubricious gel carrier comprising a cellulose polysaccharide gel. 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 and sodium carboxymethyl cellulose (CMC). WO-A-93/15721 is silent on the source of CMC. CMC 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. The viscosity of the gel is fine-tuned between 20 - 200 kcP (Pa.s). It is suggested that at lower gel viscosities the particles do not remain in suspension. In order to obtain a gel within the desired viscosity range the carboxymethyl cellulose is first mixed with about 25 wt% glycerine.

However, the choice of glycerine for optimizing the gel carrier particles of the polysaccharide is an unattractive one, since it implies the employment of relatively large amounts of foreign body materials into the body.

Similarly, US 6,716,251 concerns the use of biologically absorbable polymer microspheres or microparticles suspended in a CMC gel for filling up wrinkles, thin lines, skin cracks and scars, etc.. In order to guarantee a good dispersion of the microspheres or microparticles and the homogeneity of the gel, a surfactant is provided. It is suggested and exemplified to use poloxyethylene sorbitan monooleate (marketed under the name Tween 80) or pluronic acid. These compounds serve a purpose similar to that of glycerine in the foregoing publications, i.e. to improve the water miscibility of the CMC, but imply the same disadvantage of introducing foreign body materials into the body.

WO-A-03/007782 encompasses a biodegradable, injectable bulking agent or implant. The implant may typically comprise a cellulose derivative, such as hydroxypropylmethylcellulose (HPMC) or CMC. Again, it teaches to use a surfactant such as Tween 80 to obtain a stable suspension. The injectable further comprises glycolic acid. The only example involves HPMC and Tween 80.

In the field of bone regeneration injectibility is not an issue. There, the aim is rather to insert as many tissue filler particles as possible. Hence, for that purpose a suitable gel carrier should provide stability and gel strength with a minimum amount of carrier materials. Given the stabilizing properties and viscosity of glycerine-treated CMC, it would not be the first choice material. In the field of water retention, WO-A-99/2057 discloses an essentially fibre-free carboxymethyl cellulose with predominantly elastic properties. The focus is on its super absorbent properties, which makes it useful in various fields, such as cosmetics (e.g. shampoos, bandage, band-aid are mentioned as examples), pharmacy, foodstuffs and all kinds of technical applications, such as additives for paint, cable sealing or tunnel building and civil and underground engineering. The document is silent on the use of this particular CMC as a carrier in filler compositions, and the implications thereof.

Outside the field of tissue (re)generation, US-A-2002/0110541 describes a bone graft substitute composition that includes essentially calcium sulphate. The matrix involves CMC, but for a purpose entirely different than that in tissue repair, namely to extend the setting or curing time of the calcium sulphate to allow sufficient time for a surgeon to properly apply the bone graft substitute composition. Such a setting composition is not suitable for tissue repair. Hence, there is a continuous need to improve biocompatible implant materials for soft and hard tissue repair and augmentation, wherein the use of foreign body materials is minimized or even avoided, and wherein the gel carrier stabilizing the tissue filler material provides the composition with a gel strength and viscosity which make it injectable (in soft tissue augmentation) in minimal amounts (in hard tissue augmentation). The ideal soft tissue filler would be non-permanent, biocompatible, have minimal side effects, not require allergy testing, be easy to use/inject, be painless to inject, and be cost-effective for both the physician and the patient.

SUMMARY OF THE INVENTION It is an object of the invention to provide a biocompatible composition for use in soft and hard tissue repair and augmentation comprising a minimal amount of foreign matters, which composition has a low immunogenicity, and is resorbable over time periods of 1 - 2 years in a human being of about 40 years of age.

Traditional CMCs and related celluloses are first mixed with glycerine or other lubricants such as Tween 80 to obtain a thoroughly mixed solution before it is mixed together with water to form the gel. According to WO-A-93/15721 gel formation may easily require setting for a minimum of 4 hours to arrive at the desired viscosity. While the inventors do not wish to be bound by any theory, this is ascribed to the presence of localized crystallized domains in the CMC. The glycerine/lubricant may help in converting these domains, and thus creating the desired gelling properties.

It is found by the inventors that a pre -treatment with foreign body lubricants such as glycerine and Tween 80 can advantageously be dispensed with if the CMC-stabilised tissue filler composition suitable for soft tissue augmentation is prepared from CMC as prepared pursuant WO-A-99/2057.

It is found that this particular CMC is not only attractive in that it no longer requires foreign body materials such as glycerine, but is also found that it exhibits properties which make it particularly useful as a gel carrier in tissue filler compositions in terms of injectibility and concentrations required to stabilize the tissue filler material, in which it distinguishes from glycerine-treated CMC conventionally applied. Although speculative, these findings may somehow be linked to its water retention capacity for which it is promoted in the aforementioned PCT application

Secondly, there appears to be a direct link between the CMC in question and its viscosity behaviour, which renders it especially suitable for the purpose of the present invention: Viscosity plays an important role both in soft as well as hard tissue augmentation, albeit in different ways: For soft tissue repair it is required that the tissue filler composition is easily injectable. For that purpose, stabilization of the tissue filler material should be achieved at gel viscosities as low as possible. For hard tissue repair, where injectibility does not play a role, as much particles are to be inserted in the body as possible. Thereto, stabilization of tissue filler material should be achieved using as little gel carrier as possible.

It is found that the CMC of the present invention can easily realize both, in contrast to the traditional CMCs. In the context of the invention, with "stability" it is meant that the tissue filler material remains in suspension for more than two weeks under normal storage conditions, preferably even more than two months. Inevitably, a curable bone graft substitute composition comprising calcium sulphate such as taught in US-A-2002/0110541 is not comprised in the term "tissue filler composition" of the invention. A composition suitable for tissue filling is non-curable. A CMC-stabilized tissue filler composition with the CMC of the present invention is sufficiently stabilized even if the gel carrier exhibits a viscosity of 5 - 7 kcP (Pa.s), far lower than the allegedly required lower level of at least 20 kcP (Pa.s), as measured with a Brookfield Viscometer with RU#7 spindle at 16 rpm. The minimum of 20 kcP (Pa.s) reported in the art for glycerine-treated CMC is the result of the interplay between the requirements of injectibility on the one hand and stability of the tissue filler material on the other hand. While it would be more favoured in terms of the first to use lower viscosities, glycerine-treated CMC is not able to provide stability at concentrations corresponding to those viscosity levels. It is evidenced in the accompanying examples that the CMC of the invention advantageously distinguishes there from.

DETAILED DESCRIPTION OF THE INVENTION

The invention thus pertains to a tissue filler suspension containing tissue filler material, preferably augmentation particles, wherein said suspension further contains carboxymethyl cellulose (CMC) and is free from glycerine.

In a further aspect, the tissue filler suspension of the invention is free from surfactants, including the aforementioned glycerine, for reasons stated above. The term "surfactant" comprises all chemical means applied to improve the water miscibility of the CMC, which surfactants reduce the surface tension in solution. It is especially preferred to avoid those surfactants such as polysorbates, such as polyoxyethylene sorbitan, pluronic acid, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan trioleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan tristearate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monolaurate. Many of those surfactants listed are commercially available as Tween, such as Tween 80.

More generally, the invention pertains to a tissue filler suspension containing tissue filler material, preferably augmentation particles, wherein said suspension further contains carboxymethyl cellulose (CMC) and is free from foreign body materials other than said CMC. "Foreign body materials" particularly includes those substances which are not normally present in a human being, or for that matter, bioincompatible. Obviously, in the context of the invention, CMC is the only exception thereto.

Throughout the description and claims, the term "gel" or "suspension" are considered interchangeable, and refer to the aqueous glycerine- free mixture of tissue filler material and CMC .

Each of the above embodiments may comprise one or more of the additional features as discussed in more detail here below. Carboxymethyl cellulose

As already recognized in the art, of all existing cellulose ether variants carboxymethyl cellulose has proven especially beneficial in stabilizing the tissue filler matrix, since it provides a change in the surface morphology of the tissue filler material which is believed to enhance the physical and biocompatible properties of the material. Unlike other lubricants, it is able to suspend the tissue filler material for an indefinite amount of time and eases further processing and injection. For example, the force required for injection is significantly and conveniently smaller than if conventional glycerine- treated CMC would be used without the glycerine or surfactant. Hence, the invention is limited to CMC from the class of ionic and non-ionic cellulose ethers which may be prepared following the preparation method according to WO- A-93/15721.

The CMC suitable for use in accordance with the invention - thus, without the necessity to pre -treat it with glycerine or other surfactants - distinguishes from other carboxymethyl celluloses conventionally applied in augmentation in its rheological properties, especially its elastic properties. These changes may well be related to its preparation process, which differs from that of corresponding prior art cellulose ethers in that the CMC of the present invention is no longer produced using alkaline conditions. Instead, in aqueous solution, even without crosslinking agents, the CMC of the present invention forms high-strength gels.

a. Water miscibility

Linked thereto, the CMC of the invention also has a water-miscibility which is improved over that of conventional Tween- or glycerine-treated CMC. In the context of the invention, the CMC is preferably soluble in water to an extent of at least 99.5%. In order to determine the extent of water solubility, the skilled person is referred to the method as laid down on page 11 lines 13 - 24 of WO-A-99/20657, quoted here below:

In order to determine the complete solubility in water, an amount of air-dried, purified cellulose ether was weighed in which corresponded to 500 mg of the absolutely dry substance, and was dissolved in 199.5 ml distilled water. This solution was filtered completely, under suction, through a G2 glass filter funnel which had been weighed after drying to constant weight at 120 0C. The filter crucible was subsequently washed five times with 100 ml distilled water each time, in order to remove portions of dissolved cellulose ether adhering thereto. The glass filter crucible was dried to constant weight at 120 0C. again and was re-weighed. The insoluble fraction was determined from the difference in weight, and the percentage content of soluble cellulose ether was calculated therefrom. Cellulose ethers which had a water-soluble fraction greater than 99.5% were deemed to be completely soluble within the range of accuracy of the measurements.

b. Viscosity

The CMC of the present invention may be characterized by its viscosity and water- retention capacity, since these features are thought to contribute to its use as a gel carrier in tissue filler composition predominantly.

The viscosity of a 1 wt% CMC in water is preferably at least 9,000 mPa.s (cP) as determined by a Brookfield, LVT, 30 rpm, spindle 4, at a temperature of 25 °C. This is far higher than the 1000 - 2800 cP (mPa.s) reported in WO-93/15721 for conventional CMC when used in combination with glycerine or surfactant. Note that the above test involves CMC alone, not the tissue filler composition comprising CMC. The CMC of this invention remains stable at a lower viscosity than conventional CMC. As mentioned above, it is the lower viscosity that makes the CMC of the present invention extremely useful for injecting. Connected to that same viscosity profile, CMC also appears to achieve satisfactory stability and gelling to the tissue filler material even at very low concentrations, rendering it a first-choice material for hard tissue regeneration.

c. Water retention

In terms of water retention, a suitable CMC may exhibit an absorbency of at least 30 g liquid/gram CMC, as analyzed following the test described on page 13 line 11 - page 14 line 7 of WO-A-99/20657. In summary, swelling capacitiy was determined by introducing 200 mg carboxymethyl cellulose into a tea bag which was subsequently closed. 150 ml of a 0.9% solution of sodium chloride were introduced into a crystallising dish (to give a height of fill of about 2 cm). The tea bag was placed horizontally on the salt solution for 10 minutes. After allowing it to drain for 1 minute, the swelling capacity was determined by a final weighing. The procedure was repeated using an empty tea bag as a zero sample. The absorption was calculated from the following expression: Absorption = [ (final weight) - (zero sample - initial weight) ] / (CMC weighed in)

High values denote very good values of water retention. Before testing, the samples were adjusted to a particle size distribution of 100%<2 mm, 100%<0.5 mm and

80%<0.075 mm by grinding and sieving. The swelling capacity was firstly determined on the native material, i.e. on the material without temperature loading, and secondly after thermal loading (15 minutes) at 180 0C. Typically, the absorption was higher than 30, more preferably higher than 35 g/g.

d. Source

The CMC of the invention may also be characterized by its source. It is preferably produced from lignocelluloses and pine celluloses, linters or crude linters, as well as mixtures thereof. The CMC is essentially fibre-free, i.e. having a fibre content of less than 1 wt%. In theory, it is also possible to use CMC derived from cotton. The residual salt content of the CMC is preferably lower than 3 %. The particle size distribution of the CMC employed in the present invention is preferably characterized by an upper limit of 2 mm. More preferably all CMC particles are smaller than 0.5 mm, most preferably at least 80% is smaller than 0.075 mm. This may be achieved by grinding and sieving.

e. Degree of polymerisation, degree of substitution

The carboxymethyl cellulose preferably has an average degree of polymerisation of at least 1000, preferably 2000 - 3500. CMC is further characterized by its degree of substitution (AS) by ether groups, i.e. carboxymethyl groups. AS denotes the number of substituted hydroxyl groups per anhydroglucose unit in the cellulose unit. The AS should be at least 0.2, since at lower values the product is insoluble in water.

f. Transmission

A particularly suitable CMC candidate may be characterised by a transmission of more than 99.5 %, preferably at least 99.9 %, wherein the fraction of transmitted light is defined as a percentage of the incident light during passage through an optical cell filled with 0.5 wt% solution of aqueous CMC (d=10 mm, wavelength λ - 500 nm (Hitachi spectrophotometer, Model 101, Hitachi Ltd. Tokyo).

g. Storage modulus Rheological properties - other than viscosity - which are different from those of prior art CMC are the storage modulus G' and the loss modulus G". Other related rheological parameters are also indicative of a change of properties, such as the complex viscosity η*, the phase angle δ and the loss factor tan δ as a function of the angular frequency Ω. In particular, for aqueous solutions of a maximum CMC concentration of 0.5 wt%, the loss factor tan δ is less than that of prior art cellulose, and is substantially irrespective of the angular frequency, and at an angular frequency of 1 Hz is less than 1.0, and in particular less than 0.8. More details and comparative tests are given in WO- A-99/20657. Although the test gives a good indication of the CMC as provided in the cited patent publication, in the process of the invention is better to characterize the viscoelastic properties of the CMC at the minimum concentration at which the loss factor tan δ is in fact higher than 1, indicative of permanent viscoelastic properties. It is found that the CMC of the present invention shows such permanent viscoelastic behaviour - for instance when measured at an angular frequency of 1 Hz - at a concentration higher than 0.5 wt%, preferably at least 0.8 wt%. As a reference, for conventional glycerine -based CMC such behaviour is typically only achieved at much higher concentrations, even more than 2 wt%, sometimes even 3 wt%. Hence, the CMC of the invention may be characterized by a loss factor tan δ of at most 2 wt% at 1 Hz, to distinguish from conventional CMCs.

h. Preparation route

The CMC of the invention may also be characterized by its preparation process, as it is described in great detail in WO-A-99/20657. In summary, the CMC may be used as obtainable by performing the following preparation steps: a) providing cellulose with an average degree of polymerisation of at least

1000, preferably 2000 - 3500; b) treatment of the cellulose according to step a) with an aqueous-organic suspension medium; and c) etherification, purification, drying and manufacture of the cellulose ether. The aqueous-organic suspension medium applied in step b) is preferably isopropanol-water, acetone-water, methanol-water, ethanol-water or t-butyl alcohol- water, or mixtures thereof, which have a total water content - with respect to the cellulose, suspension medium, sodium hydroxide and etherification agent (such as chloroacetic acid or vinylsulphonic acid) of 11 - 28 vol%, more preferably 12.5 - 25 vol%, particularly 13 - 20 vol%, and an amount of alkali, e.g. sodium hydroxide, of at least 1.8-2.6 mol, preferably 2.0-2.5 mol, especially 2.1-2.4 mol/mol glucose units.

A suitable amount of caustic solution is required in step b) to achieve a low fibre content of less than 1%. The alkali also serves to convert crystalline regions of the cellulose into amorphous regions. Hence, step b) may also be referred to as an alkalification step, although being different from the alkalification step as traditionally applied in the field of cellulose ether manufacture. The function of the water in the suspension medium is to make the cellulose easily accessible to the reagents, and at the same time facilitate a satisfactory swelling capacity. The skilled person will find help in WO-A-99/20657 to determine the optimum water balance within the aforementioned range in order to control the rheological properties of the CMC for application in the present invention.

Although the alkalification and etherification are addressed as different steps b) and c), the etherification agent may be present, on its own or optionally with additional amounts of a second etherification agent, before or during alkalification. Normally, the etherification agent is added after the addition of the total amount of alkali. Caustic soda or caustic potash are preferably used as the alkali.

The etherification step c) involves an amount of 0.4 - 2.5 mol, particularly 0.5 - 1.8 mol, preferably 0.6 - 1.5 mol etherification agent per mol glucose. The etherification agent is preferably monochloroacetic acid. The etherification and subsequent processing steps are performed in a customary, known manner. Like alkali in step b), the etherification agent also affects the conversion of crystalline domains in the CMC. However, it is important that etherification is performed so that a cellulose ether obtains the desired average degree of substitution (AS). The AS is preferably lower than 1.5, since higher substitution levels result in no further improvement of the properties as regards to solubility and absorbance. Etherification then becomes increasingly uneconomic, and the increased solubility can results in problems during work up.

A CMC which fulfils all of the aforementioned characteristics and is thus preferred is Walocel® CRT, as it is commercially available with Wolff Cellulosics GmbH (Walsrode, Germany).

The invention pertains to the use of a CMC characterized by one or more of the foregoing features for stabilizing tissue filler material in soft and hard tissue augmentation, and in regeneration of cells.

Tissue filler material

The properties of the tissue filler material, also referred to as "augmentation material" if intended for soft or hard tissue augmentation, are adapted to their particular use. If the use rests in soft or hard tissue augmentation, it is preferred that the tissue filler material is augmentation material comprising ceramic particles and/or biodegradable polymers. The term "biodegradable polymers" is understood to comprise polylactic acid (PLA) and Polyactive™. Polyactive™ may be used in a biodegradable polymeric drug delivery system, and represents a series of poly(ether ester)multiblock copolymers, based on poly(ethylene glycol) (PEG) and poly(butylene terephthalate) (BPT). Polyactive™ may be used as marketed by Octoplus (Leiden, the Netherlands). Hence, the tissue filler material preferably comprises polylactic acid, Poly Active™ and/or calcium phosphate.

The tissue filler material preferably comprises ceramic particles, more preferably comprising calcium phosphate, calcium silicate, calcium carbonate or fluorides. For sake of completeness, it is repeated here that calcium sulphate, which cures upon contact with water, is not a suitable tissue filler material according to the invention.

The ceramic material is preferably a calcium phosphate, particularly comprising hydroxyapatite (HA), also known as basic calcium phosphate, which is the natural mineral phase of teeth and bones. As an implant material, granular hydroxyapatite, has proven to be highly compatible in tissue. Known hydroxyapatite derivates are included. Examples include, but are not limited to, tetracalcium phosphate, calcium pyrophosphate, tricalcium phosphate (TCP), 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 sizes and porosities. The choice of material is regardless of the microstructure, protonation status of the phosphate, or extent of hydration. While the mineral content of bone could be harvested and purified for this purpose, the use of industrially produced calcium phosphate mineral particles is preferable, because of its more predictable quality. The preparation of the ceramic particles may involve an agglomeration step.

The preferred ceramics for use as augmentation particles comprises HA, fluorapatite, octacalcium phosphate and TCP.

Alternatively, the tissue filler material may be living cells that can be used for regenerating connective and soft tissue.

a. Soft tissue augmentation material For soft tissue augmentation, the features of the tissue filler material are predominantly selected for its injectibility. 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 %.

Where lower resorbability rates are desired, it is preferred that the augmentation material resembles 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 injectibility. 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 μm 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 hydroxyapatite typically at a rate of 15 μm/year. The resorbtion time of the injected mass depends on the actual particle size. The upper limit of the augmentation particle size is determined by its injectibility, meaning that the composition can easily be injected through a syringe intradermally or subcutaneously. If introduced into soft tissue by injection 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 average range for injection is from about 20 to 150 μm, more preferably from 25 - 100 μm. The particles are typically in the range of 35 - 50 μm to minimize the possibility of particle migration by phagocytosis and to facilitate injectibility. Throughout the text, particle sizes refer to the largest dimension, unless stated otherwise.

To further improve injectibility, it is preferred to use 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. Hence, it is preferred that the size difference between the largest and the smallest soft tissue augmentation particle does not exceed about 35 μm. Further, it may be desirable to minimize surface porosity to below 30%; with elimination of jagged irregular surfaces, the ability of the smooth round particles to flow easily in contact with each other is maximized.

b. Hard tissue augmentation material

For hard tissue augmentation, the tissue filler material is preferably large and to some extent porous. The augmentation particles are then preferably between 100 μm and 4 mm, preferably between 1 - 1.5 mm.

The surface porosity 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. Filler composition and its preparation

Again, the actual CMC-stabilized tissue filler suspension is determined by its use. It is already argued above that the minimum CMC concentration in water is 0.5 wt%, exhibiting the required loss factor tan δ > 1. For soft tissue augmentation, the augmentation material, preferably ceramic particles, are present in an amount of 50 - 90 wt%, while the gel carrier material and water are present in an amount of 10 - 50 wt%, based on the total weight of the composition. The actual amount of CMC in the composition preferably varies between 0.5 - 3.5 wt%, more preferably 1 - 2 wt%. For reasons of injectibility, the suspension has a gel viscosity of smaller than

30,000 cP (mPa.s), as measured by Brookfϊeld Viscometer RVDII and spindle 6 at 20rpm. The lower limit may be as low as 6500 cP (mPa.s). The viscosity of the gel is preferably higher than 8000 cP (mPa.s), preferably lower than 20000 cP (mPa.s). Best results in terms of processibility are obtained if the gel viscosity is lower than 18000 cP (mPas). These viscosity numbers are taken at 25 °C.

For hard tissue augmentation, the amounts of augmentation material may be even larger, from 50 - 95 wt%. Gel material and water preferably form 5 - 50 wt%. Even with as low as 5 wt% gel carrier material and water satisfactory stabilization is achieved. The actual amount of CMC in the composition preferably varies between 0.5 - 3.5 wt%, more preferably 1 - 2 wt%.

Next to tissue filler material and gel carrier, the composition optionally comprises an amount of active ingredients. These 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. Another suitable active ingredient is a local anaesthetic agent. For the purpose of osteogenesis, the tissue filler material 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 invention also pertains to a method for preparing the above tissue filler composition by mixing CMC and tissue filler material, preferably augmentation material, most preferably ceramic particles, in the required proportions.

Thereto, it is preferred to first dissolve the CMC in water. The CMC of the present invention brings the additional invention in that no setting time is required before mixing in the tissue filler material. This is in contrast to what is reported in relation to the conventional glycerine-treated CMCs, such as the minimum 4 hours in WO-A-93/15721. This is probably related to the excellent water-miscibility and water retention capacity of the CMC of the present invention. After preparation, the suspension may be sterilized, ordinarily accomplished by autoclaving at temperatures of 115 - 130 °C for 20 minutes - 1 hour, typically at about 2 bar. Sterilization may result in a reduction of the gel viscosity, provided that the end viscosity is within the aforementioned ranges.

Use

Soft tissue repair and augmentation according to the present invention encompasses the use of the biocompatible composition in the treatment of skin deficiencies caused by diseases such as acne, cancer, trauma and lipodystrophy syndrome. It also includes the treatment of scars on or within the skin caused by accidents, wounds and injuries. The skin deficiencies may be the result of the treatment of a disease. The dermal augmentation material 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.

As discussed above extensively, the biocompatible composition may also 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 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 gel and other optional components are packaged in ready-to-use syringes, for instance those as described in WO-A-93/15721.

EXAMPLES

Example 1 - Preparation of the gel

Water is filled into a suitable container and brought there under slow agitating to its boiling temperature. Then, under further, strong agitation 1.8wt% Walocel CRT 20,000 (Wolff Cellulosics GmbH (Walsrode, Germany)) was added. The resulting gel was mixed to completely dissolve the CMC. Subsequently, enclosed air was removed by means of vacuum and/or ultrasonic. The viscosity was approximately 20,000 cP (mPa.s), measured with a Brookfield Viscometer RVDII and spindle 6 at 20rpm.

Example 2 - Preparation of the gel

Example 1 was repeated using a 1.4wt% Walocel CRT 50,000. The resulting gel had a viscosity of approximately 16,000 cP (mPa.s), measured with a Brookfield Viscometer RVDII and spindle 6 at 20rpm.

Example 3 - Preparation of the augmentation composition

100ml gel of as in example 1 or 2 was mixed with 130,6g hydroxyapatite granulates

(20-45 μm; Cam implants BV (Leiden, The Netherlands)). Subsequently, enclosed air was removed by means of vacuum and/or ultrasonic. The viscosity was approximately 15,000 cP (mPa.s), measured Brookfield Viscometer RVDII at 20rpm.

Comparative example I - Preparation of a conventional CMC gel with glycerine 75 ml cold water was filled into a suitable container. As a CMC source 2.25g Cekol 50.000 was used, which was mixed with 25g glycerine until a homogeneous mass developed. The mixture of CMC and glycerine was then added to the water under agitation. The produced gel exhibited a minimum setting time of 4 hours. Subsequently, enclosed air was removed by means of vacuum and/or ultrasonic. The viscosity was >80,000 cP (mPa.s), measured with a Brookfield Viscometer RVDII and spindle 6 at 20rpm.

Comparative example II - Conventional CMC gel without glycerine

The recipe given in comparative example I was repeated, but no glycerine was added. However, mixing was problematic. High shearing stresses and long time were required to achieve any result at all.

Further, upon mixing of 100ml gel of the gel with 130,6g hydroxyapatite granulates (20-45 μm; Cam implants BV (Leiden, The Netherlands)) the particles immediately precipitated, the gel thus not fulfilling its carrier function.

Comparative example III - Sigma- Aldrich CMC with and without glycerol 25wt% Glycerine (produced by Acros) in water was filled into a suitable container and brought there under slow agitating to 750C. Then, under further, strong agitation 2.8wt% Sigma- Aldrich (product code 419303) was added, based on the total weight of the water, CMC and glycerine; and after dissolving the gel was cooled down to 250C . The next day the resulting gel had a viscosity of approximately 13400 mPa.s, measured with a Brookfield Viscometer RVDII and spindle 6 at 20rpm.

The experiment was repeated without glycerine. Like in comparative example II, mixing was problematic. High shearing stresses and long time were required to achieve any result at all.

Claims

1. A tissue filler suspension containing tissue filler material, wherein said suspension further contains carboxymethyl cellulose (CMC) and is free from glycerine and surfactant.
2. A tissue filler suspension containing tissue filler material, wherein said suspension further contains carboxymethyl cellulose (CMC) and is free from foreign body materials other than said CMC.
3. The tissue filler suspension according to claim 1 or 2, wherein said tissue filler material is augmentation material comprising ceramic particles and/or biodegradable polymers.
4. The tissue filler suspension according to claim 3, wherein said tissue filler material comprises polylactic acid, PEG-BPT copolymer and/or calcium phosphate.
5. The tissue filler suspension according to any one of the preceding claims, containing 1 - 3.5 wt% CMC.
6. The tissue filler suspension according to any one of the preceding claims, being stable for more than two weeks.
7. The tissue filler suspension according to any one of the preceding claims, wherein said CMC exhibits a viscosity of at least 9,000 mPa.s as determined by a
Brookfield, LVT, 30 rpm, spindle 4, at a temperature of 25 °C, if measured in an 1 wt% water solution of said CMC.
8. The tissue filler suspension according to any one of the preceding claims, having a viscosity of smaller than 30,000 cP (mPa.s), as measured by Brookfield Viscometer
RVDII and spindle 6 at 20rpm and 25 °C.
9. The tissue filler suspension according to any one of the preceding claims, having a viscosity of at least 6500 cP (mPa.s), as measured by Brookfield Viscometer RVDII and spindle 6 at 20rpm and 25 °C.
10. The tissue filler suspension according to any one of the preceding claims, wherein said CMC exhibits an absorbency of at least 30 g liquid/gram of cellulose ether.
11. The tissue filler suspension according to any one of the preceding claims, wherein said CMC is obtainable by performing the steps of: a) providing cellulose with an average degree of polymerisation of at least
1000, preferably 2000 - 3500; b) treatment of the cellulose according to step a) with an aqueous-organic suspension medium; and c) etherifϊcation, purification, drying and manufacture of the cellulose ether.
12. The tissue filler suspension according to any one of the preceding claims, having a gel viscosity of lower than 20,000 mPa.s, as measured by Brookfield Viscometer RVDII and spindle 6 at 20rpm.
13. The tissue filler suspension according to any one of the preceding claims, for medical use.
14. The tissue filler suspension according to claim 13, for use in soft or hard tissue augmentation.
15. Use of the tissue filler suspension according to any one of claims 1 - 12 in cosmetics.
16. The tissue filler suspension according to claim 1 or 2, wherein said tissue filler material comprises living cells for regenerating connective tissue.
17. A process of cosmetically improving the bodily appearance of a mammal, comprising introducing to the mammal's body subcutaneously or intradermally the composition according to any one of claims 1 - 12 or 16 in injectable form.
18. A kit of parts, comprising ready-to-use syringes with a) augmentation particles for soft or hard tissue augmentation; and b) an aqueous gel of CMC free from glycerine and surfactant.
PCT/NL2007/050605 2006-11-29 2007-11-29 Carboxymethyl cellulose-stabilised tissue filler and its preparation and use WO2008066382A1 (en)

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WO2003007782A2 (en) * 2001-06-29 2003-01-30 Medgraft Microtech, Inc. Biodegradable injectable implants and related methods of manufacture and use
US6716251B1 (en) * 1997-06-13 2004-04-06 Aventis Pharmaceuticals Holdings, Inc. Implant for subcutaneous or intradermal injection

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US6716251B1 (en) * 1997-06-13 2004-04-06 Aventis Pharmaceuticals Holdings, Inc. Implant for subcutaneous or intradermal injection
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