WO2008066657A2 - Compositions, dispositifs et procédés de modification d'un tissu mou - Google Patents

Compositions, dispositifs et procédés de modification d'un tissu mou Download PDF

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Publication number
WO2008066657A2
WO2008066657A2 PCT/US2007/023226 US2007023226W WO2008066657A2 WO 2008066657 A2 WO2008066657 A2 WO 2008066657A2 US 2007023226 W US2007023226 W US 2007023226W WO 2008066657 A2 WO2008066657 A2 WO 2008066657A2
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WO
WIPO (PCT)
Prior art keywords
polymer
scc
composition
reservoir
radical
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PCT/US2007/023226
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English (en)
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WO2008066657A9 (fr
WO2008066657A3 (fr
Inventor
Edward E. Schmitt
John F. Krumme
Christian Walton
Original Assignee
Aesthetic Sciences Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Aesthetic Sciences Corporation filed Critical Aesthetic Sciences Corporation
Priority to US12/114,194 priority Critical patent/US20090124996A1/en
Publication of WO2008066657A2 publication Critical patent/WO2008066657A2/fr
Publication of WO2008066657A3 publication Critical patent/WO2008066657A3/fr
Priority to PCT/US2008/072310 priority patent/WO2009021020A1/fr
Priority to EP08797262A priority patent/EP2183003A1/fr
Priority to AU2008283868A priority patent/AU2008283868B2/en
Priority to US12/187,964 priority patent/US20090198183A1/en
Priority to PCT/US2008/072558 priority patent/WO2009021158A1/fr
Publication of WO2008066657A9 publication Critical patent/WO2008066657A9/fr
Priority to US12/477,527 priority patent/US20090240200A1/en
Priority to US12/871,405 priority patent/US8343132B2/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/142—Pressure infusion, e.g. using pumps
    • A61M5/145—Pressure infusion, e.g. using pumps using pressurised reservoirs, e.g. pressurised by means of pistons
    • A61M5/1452—Pressure infusion, e.g. using pumps using pressurised reservoirs, e.g. pressurised by means of pistons pressurised by means of pistons
    • A61M5/14526—Pressure infusion, e.g. using pumps using pressurised reservoirs, e.g. pressurised by means of pistons pressurised by means of pistons the piston being actuated by fluid pressure
    • 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
    • A61L27/14—Macromolecular materials
    • 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
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/06—Flowable or injectable implant compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/28—Syringe ampoules or carpules, i.e. ampoules or carpules provided with a needle
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/31—Details
    • A61M5/32—Needles; Details of needles pertaining to their connection with syringe or hub; Accessories for bringing the needle into, or holding the needle on, the body; Devices for protection of needles
    • A61M5/34—Constructions for connecting the needle, e.g. to syringe nozzle or needle hub
    • A61M5/347—Constructions for connecting the needle, e.g. to syringe nozzle or needle hub rotatable, e.g. bayonet or screw
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/44—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests having means for cooling or heating the devices or media

Definitions

  • This invention relates to compositions, methods and devices for modifying soft tissue in human beings and other mammals.
  • compositions known for this purpose comprise for example collagen or a derivative thereof, hyaluronic acid, polylactic acid, hydroxymethylcellulose, hydroxyapatite and expanded polytetrafluoroethylene.
  • Devices for dispensing such compositions are also known. Reference may be made for example to
  • the present invention provides novel compositions which comprise side chain crystalline (SCC) polymers (as hereinafter defined) and which are suitable for use in the modification of the soft tissue of mammals.
  • SCC side chain crystalline
  • the novel compositions unlike the known compositions, can remain effective for extended periods of time, or, if desired, for selected shorter periods.
  • the invention provides novel injection devices suitable for dispensing such compositions, and other purposes.
  • the invention provides novel SCC copolymers, novel intermediates for making SCC polymers, novel methods of making SCC copolymers, and novel components for use in injection devices.
  • the invention also includes methods which comprise placing a composition comprising an SCC polymer in a human being.
  • the composition can for example be placed in or close to the stratum corneum to change the contours of the skin for cosmetic and/or reconstructive purposes (the term skin being used herein to include skin defects such as, for example, acne scars); or it can be placed at another location for reconstructive purposes, for example to modify a sphincter, e.g. to control urinary or fecal incontinence.
  • compositions which (a) comprise a side chain crystalline (SCC) polymer,
  • a reservoir for a composition to be dispensed the reservoir having an outlet to which a needle can be, or is, fixed,
  • (1 ) comprise (a) 3 to 15%, by weight, based on weight of the polymer, of one or more first polymer blocks each of which (i) has a number average molecular weight (Mn) of less than 5000, and
  • (ii) comprises at least 70%, based on the weight of the block, of repeating units having the formula -Y(Rc)-, wherein each of the Y radicals is a radical forming part of the backbone of the polymer, and each of the -Y(Rc)- radicals contains a side chain Rc radical which is a high temperature crystallizable (HTC) radical (as hereinbefore defined), and
  • HTC high temperature crystallizable
  • Hard block oligomers which are suitable for use in step (A1 ) or (A3) of (E); which have an Mn of less than 5,000 and a polydispersity less than 3; and which contain a reactive linking group through which the oligomer can be joined to the second blocks (the soft blocks), or a functional group which can be converted into such a reactive linking group.
  • G Soft block precursors which are suitable for use in step (A2) or (A3) of (E), and which comprises a plurality of repeating units of the formula -Z(Rz)-, at least one of the Z radicals including a bioerodable linking group and/or a functional group which can be reacted to form a linking radical which is bioerodable.
  • Novel components which can form part of an injection device as in (B), for example
  • a needle comprising a fitting which can be fixed to the outlet of a reservoir, and an electrical heater substantially surrounding the fitting;
  • a reservoir which comprises an outlet, and, adjacent to the outlet, a component composed of a magnetically permeable material
  • a needle which comprises a fitting for securing the needle to a reservoir, the fitting comprising a magnetically permeable material.
  • composition comprising an SCC polymer in the mammal, the composition preferably being a composition as defined in (A), and/or comprising an SCC polymer as defined in (C) or
  • SCC polymer is used herein to denote a polymer which comprises a plurality of repeating units having the formula -Y(Rc)-, wherein each of the Y radicals is a radical forming part of the backbone of the polymer, and each of the -Y(Rc) — radicals contains a crystallizable side chain Rc radical such that the Rc radicals can crystallize together.
  • the resulting polymer has a crystalline melting point which results from the melting of Rc radicals which have crystallized together.
  • SCC polymers also contain a plurality of repeating units having the formula -Z(Rz)- , where Z is a radical forming part of the polymer backbone and -Z(Rz)- does not contain an Rc radical; thus, Rz is not an
  • Rc radical As further discussed below, a wide variety of Y, Rc, Z and Rz radicals can be present in an SCC polymer.
  • SCC polymers melt over a narrow temperature range, and at a temperature which is chiefly determined by the Rc radicals.
  • the melting point is little influenced by the molecular weight of the polymer (unlike conventional crystalline polymers, whose crystallinity results from crystallization of main polymer backbone).
  • homopolymers of n-alkyl acrylates in which the n-alkyl group contains 14, 16, 18, 20, 22, 30, 40 and 50 carbon atoms typically have peak melting points (Tp, as defined below) of about 20, 36, 49, 60, 71 , 76, 96 and 102 0 C respectively, while the homopolymers of the corresponding n-alkyl methacrylates typically have Tp's of about 10, 26, 39, 50, 62, 68, 91 and 90 5 0 C respectively.
  • Random polymers containing -Z(Rz)-- units typically have somewhat lower melting points; block copolymers in which the Y(Rc) units are grouped together typically have intermediate Tp's.
  • the SCC polymer, and the other ingredients, if any, of the composition to be placed in a human being or other mammal are preferably such that
  • the composition can be maintained at a relatively high temperature which (i) is above the body temperature of the mammal at the location into which the composition is to be placed, but is not too hot to be tolerated by the mammal, and
  • the composition is such that, after it has been placed within the mammal, it takes a substantial time, e.g. at least 5 minutes, to reach equilibrium within the mammal. During this time, even if the composition has cooled to below its melting point, there is little or no crystallization of the SCC polymer. This makes it possible for the shape of the composition under the skin, and in consequence the shape of the skin over the composition, to be changed by pressure exerted selectively on the exterior of the skin.
  • the SCC polymers defined in (C) above are novel per se. They (1 ) comprise, e.g. consist essentially of,
  • first polymer blocks (often referred to herein as hard blocks), each of the first polymer blocks (i) having a number average molecular weight (Mn) of less than 5000, preferably less than 3000, e.g. less than 1500, and (ii) comprising at least 70%, preferably at least 85%, based on the weight of the first polymer block, e.g.
  • Mn number average molecular weight
  • each of the Y radicals is a radical forming part of the backbone of the polymer, and each of the - Y(Rc)- radicals contains a side chain Rc radical which is a high temperature crystallizable (HTC) radical (as hereinafter defined), and
  • HTC high temperature crystallizable
  • HTC high temperature crystallizable
  • the polydispersity of the novel copolymers is preferably less than 3, particularly less than 2.
  • the SCC polymers defined in (D) above are novel per se.
  • at least some of the Y radicals, and/or at least some of the Z radicals, when present, comprise a linking group which is bio-erodable, i.e. which, when the SCC polymer is present in a human body, can be weakened or destroyed, e.g. by hydrolysis, by substances which are present in the human body, particularly aqueous fluids.
  • bio-erodable linking groups can be controlled in the preparation of the polymer, in order to make an SCC polymer which has a desired erodability over the course of time.
  • bioerodable linkages include ether linkages and phosphorus-containing linkages, e.g. phosphates.
  • the polydispersity of these bio erodible polymers is preferably less than 6, particularly less than 4. At least some of the linkages between the hard blocks and the soft blocks, and/or within the soft blocks of the SCC polymers as defined in (C) can be bioerodable.
  • the compositions as defined in (A) contain one or more SCC polymers which
  • (1 ) have a peak melting point (Tp) of 33 to 48°C, preferably 35 to 46 0 C, e.g. 37 to 43°C; and/or (2) are as defined in (C) and/or (D) above.
  • Tp peak melting point
  • the SCC polymer can be selected so that the composition retains its desired shape for a desired period of time, for example for a time which is substantially longer than the time for which many of the compositions now in use are effective, and/or for a time which depends upon the bioerodability of the polymer.
  • An advantage of the SCC polymer compositions is that, after they have been placed in a human being and have assumed a substantially stable shape, that shape can be changed, or some or all of the composition can be extracted, by (A) heating the composition to a temperature above its melting point, and (B) exerting pressure on the skin to change the shape of the composition and/or extracting at least a portion of the composition through an opening in the skin.
  • steps (B1 ) and (B2) of the method described in (E) the formation of the polymeric block on the oligomer or precursor can be effected by addition or condensation polymerization.
  • the oligomers described in (F) above correspond to the first polymeric blocks (the hard blocks) in the SCC polymers disclosed in (C) above.
  • the oligomer (i) has an Mn of less than 5,000, preferably less than 3,000, e.g. less than 1 ,500, (ii) comprises at least 70%, preferably at least 85%, based on the weight of the oligomer, e.g.
  • each of the Y radicals is a radical forming part of the backbone of the polymer, and each of the -Y(Rc)- radicals contains a side chain Rc radical which is an HTC radical as hereinbefore defined, and (iii) comprises a reactive linking group through which the oligomer can be joined to the second polymeric blocks (the soft blocks), or a functional group which can be converted into such a reactive linking group.
  • the polydispersity of the oligomers is preferably less than 3, particularly less than 2.0, e.g. less than 1.7, preferably less than 1.4.
  • the soft block precursors described in (G) correspond to the second polymeric blocks in an SCC polymer as disclosed in (C), the precursor comprising a plurality of repeating units of the formula -Z(Rz)--, at least one of the Z radicals including a bioerodable linking group and/or a functional group which can be reacted to form a linking radical which is bioerodable.
  • the SCC block copolymers described in (C) contain only a small proportion of the - 5 Y(Rc)- radicals which could give rise to crystallinity. However, it has been found that the copolymers nonetheless have an unexpectedly useful degree of crystallinity. It has also been found that such a copolymer, if cooled beneath the skin from above its melting point to a temperature below, but not very far below, e.g. less than 1O 0 C below, its melting point, e.g. to human body temperature, takes a substantial time, e.g. at least 5 or at least 10
  • Figure 1 is an exploded perspective view of a device of the invention
  • Figure 2 is a perspective view of the device off Figure 1 when assembled
  • compositions comprising and grammatical equivalents thereof are used herein to mean that, in addition to the features specifically identified, other features are optionally present.
  • a composition " comprising” (or “which comprises”) ingredients A, B and C can contain only ingredients A, B and C, or can contain not only ingredients A, B and C but also one or more other ingredients.
  • consisting essentially of and grammatical equivalents thereof is used herein to mean that, in addition to the features specifically identified, other features may be present which do not materially alter the claimed invention.
  • at least followed by a number is used herein to denote the start of a range beginning with that number (which may be a range having an upper limit or no upper limit, depending on the variable being defined).
  • At least 1 means 1 or more than 1
  • at least 80% means 80% or more than 80%
  • the term “at most” followed by a number is used herein to denote the end of a range ending with that number (which may be a range having 1 or 0 as its lower limit, or a range having no lower limit, depending upon the variable being defined).
  • at most 4" means 4 or less than 4
  • at most 40% means 40% or less than 40 %.
  • “from 8 to 20 carbon atoms” or “8-20 carbon atoms” means a range whose lower limit is 8 carbon atoms, and whose upper limit is 20 carbon atoms.
  • the terms “plural”, “multiple”, “plurality” and “multiplicity” are used herein to denote two or more than two features.
  • first and second features this is generally done for identification purposes; unless the context requires otherwise, the first and second features can be the same or different, and reference to a first feature does not mean that a second feature is necessarily present (though it may be present).
  • reference is made herein to "a" or “an” feature this includes the possibility that there are two or more such features (except where the context excludes that possibility).
  • the term Mn denotes the number average molecular weight
  • Mw denotes the weight average molecular weight.
  • Tp denotes the peak melting temperature
  • T L denotes the temperature at which melting is complete, of a polymer, determined using a DSC calorimeter at a rate of temperature change of 10°C/min, on the second heat cycle, and typically from -10 to 150 0 C.
  • Tp is the temperature at the peak of the DSC curve.
  • T L is the intersection of the baseline of the DSC curve and the descent line of the DSC curve (defined as the tangent to the steepest part of the DSC curve above Tp).
  • substantially all the repeating units of the formula -Y(Rc)- can be the same, or there can be a plurality of different types of repeating unit which differ from each other in Y, or in Rc, or in both Y and Rc.
  • the SCC polymer also contains repeating units of the formula -Z(Rz)-, those repeating units can all be the same, or there can be a plurality of different types of repeating unit which differ from each other in Z, or in Rz, or in both Z and Rz.
  • the Y and Z radicals can be the same or different.
  • the -Y(Rc)- and-Z(Rz)- radicals can be in any desired distribution, for example randomly, or in first blocks containing only -Y(Rc)- radicals and in second blocks containing only -Z(Rz)-radicals.
  • the Rc radical will often have the general formula -S(Cy)-, where Cy is the radical which results in crystallinity, and S is a bond or a linking radical, for example a covalent bond or a divalent organic or inorganic radical, e.g. an ester, carbonyl, amide, amine oxide, hydrocarbon (for example phenylene), amino or ether radical.
  • Cy is the radical which results in crystallinity
  • S is a bond or a linking radical, for example a covalent bond or a divalent organic or inorganic radical, e.g. an ester, carbonyl, amide, amine oxide, hydrocarbon (for example phenylene), amino or ether radical.
  • the Y (and Z radicals, if present) which form the backbone of the polymer can be derived from any type of polymerization, e.g. addition and/or condensation polymerization of suitable monomers.
  • the SCC polymer can be, or can comprise sections which are, polyacrylates, polyolefins, polyethers, polyurethanes, polyesters, polyamides, polysilanes, or polysiloxanes.
  • each of the Y radicals (and each of the Z radicals, if present) normally comprises a plurality of "backbone atoms", i.e. atoms which form part of the backbone of the polymer.
  • each Y radical (and in each Z radical, if present) there is a backbone atom which is at least trivalent, generally carbon, and which carries the substituent Rc (or Rz).
  • each Y (or Z) radical includes at least one other backbone atom.
  • the other backbone atoms have a valence of at least 2. Examples of divalent backbone atoms are oxygen and sulfur. Nitrogen is an example of a trivalent backbone atom. Carbon is an example of a 4-valent atom. Any valencies of the backbone atoms which are not satisfied by the Rc (or Rz) radical can be satisfied by hydrogen radicals or other radicals.
  • the Rz radical can be a hydrogen radical.
  • Y and Z radicals will be determined by the monomers from which the polymers are derived and by the mechanism of the polymerization (e.g. addition or condensation polymerization). In some cases, all the Y and Z radicals will be the same, at least in the backbone atoms.
  • Examples of -Y(Rc)- include, without limitation, radicals having the formula:
  • R 0 is an HTC radical, e.g. derived from an n-alkyl or fluorinated n-alkyl acrylate or methacrylate in which the n-alkyl group contains 12 to 50 carbon atoms, e.g. one or more of octadecyl acrylate or methacrylate and behenyl acrylate or methacrylate;
  • R 1 is hydrogen or methyl
  • R c is an HTC radical, e.g. derived from an n-alkyl or fluorinated n-alkyl acrylate or methacrylate in which the n-alkyl group contains 12 to 50 carbon atoms, e.g. one or more of octadecyl acrylate or methacrylate and behenyl acrylate or methacrylate; 3. -CH 2 -C(RO-SOH 2 -CH 2 O -(2,2 tetrahydrofuran)-O-
  • R c is an HTC radical , e.g. derived from an n-alkyl or fluorinated n-alkyl acrylate or methacrylate in which the n-alkyl group contains 12 to 50 carbon atoms, e.g. one or more of octadecyl acrylate or methacrylate and behenyl acrylate or methacrylate; and 4, O
  • R c is an HTC radical , e.g. derived from an n-alkyl or fluorinated n-alkyl acrylate or methacrylate in which the n-alkyl group contains 12 to 50 carbon atoms, e.g. one or more of octadecyl acrylate or methacrylate and behenyl acrylate or methacrylate.
  • -Z(Rz)-- include, without limitation, radicals having the formula:
  • R z is an n-alkyl or branched chain alkyl or n- fluoroalkyl or branched chain fluoroalkyl radical containing 1-6 carbon atoms, e.g. derived from n-butyl acrylate or methacrylate.
  • linking radicals that may form part of -Z(Rz)- radicals include, without limitation, radicals having the formula:
  • R 1 is hydrogen or methyl
  • Rd is a divalent radical, e.g. -CH 2 .CH 2 -.
  • R 1 is hydrogen or methyl
  • Rd is a trivalent radical
  • R 1 is hydrogen or methyl
  • R z is an n-alkyl or branched chain alkyl group containing 1-10 carbon atoms
  • R-i is hydrogen or methyl
  • Rd is a divalent radical, e.g. -CH 2 , CH 2 -.
  • Polymers comprising the repeating units of formula Y(Rc) and, if present, repeating units of formula Z(Rz), will also contain terminal radicals, for example hydrogen or methyl.
  • Radicals 1 and 5 above are representative of radicals repeated multiple times adjacent to each other; the other radicals above are representative of radicals which can be at the end of a chain of multiple radicals, e.g. multiple radicals 1 and/or 5 above, or which can link two or more blocks of radicals of the same or different kinds, for example so as to provide a bioerodable link between those blocks.
  • polymer produced in Example 37 has the formula
  • q's may be the same or different, and the total of the q's is for example 40 to 240.
  • some or all of the Z radicals can include a linking unit which is selected for its ability to provide the SCC polymer with a desired property, e.g. to make the SCC polymer bio-erodable.
  • a linking unit which is selected for its ability to provide the SCC polymer with a desired property, e.g. to make the SCC polymer bio-erodable.
  • dihydroxy-terminated monomers, or dihydroxy-terminated oligomers or polymers which are precursors for polymeric blocks in a block copolymer can be linked to each other through a difunctional reagent such as 2-,2- diethoxy tetrahydrofuran or dichloro ethyl phosphate which results in bioerodable linkages.
  • SCC polymers which are normally hydrophobic and highly resistant to water, can be made selectively sensitive to water.
  • the first polymeric blocks (and the oligomers from which they can be derived) consist essentially of (i) units in which the Rc radical comprises an n-alkyl radical containing 16-20 carbon atoms, e.g. an n-octadecyl (also known as steary) radical, for example derived from the corresponding n-alkyl acrylate or methacrylate, e.g. n-octadecyl methacrylate, and (ii) units in which the Rc radical comprises an n-alkyl radical containing 21-30, or more, carbon atoms, e.g. a behenyl radical (i.e.
  • a linear polymethylene radical containing 22 carbon atoms for example derived from the corresponding n-alkyl acrylate or methacrylate, e.g. behenyl methacrylate.
  • the radicals (i) and (ii) can be randomly distributed in the first polymeric block.
  • Each of the first (hard block) polymeric blocks can for example contain 1 -4 of the repeating units (i) and 1-4 of the repeating units (ii).
  • the first polymeric blocks can, for example, contain on average 50-70%, e.g. 55-63%, of the behenyl radicals, based on the weight of the first polymeric blocks.
  • the SCC compositions comprising the SCC polymer hereinafter referred to as the
  • SCC polymer composition can consist of the SCC polymer, or can also contain other ingredients which do not adversely affect the functionality of the composition. In many cases, it is preferred that the composition should contain less than 5% by weight of water, preferably substantially no water.
  • the compositions can be sterilized, before being placed in the human body, e.g. by radiation.
  • the SCC polymer composition is preferably selected so that, at a temperature above TL, but at or below the temperature which can be comfortably tolerated by the human being into which the composition is to be placed, e.g. about 44°C, preferably at a temperature below 43°C or 42 0 C, the SCC composition has a viscosity such that it can be subcutaneously injected into the human being through a hypodermic needle having a gauge between 25 and 32, preferably between 27 and 30.
  • Theological properties of an SCC polymer depend upon, among other things, the extent of the crystallization of the SCC polymer.
  • the SCC polymer When all the polymer has melted, which may be for example at a temperature which is 1-7 0 C above Tp, there is no crystallinity and the polymer is a fluid.
  • the SCC polymer at the time when it is placed in the human body, is preferably a fluid having a viscosity such that it can be passed through a small tube, e.g. a tube having a gauge of 25 to 32.
  • a small tube e.g. a tube having a gauge of 25 to 32.
  • the SCC polymer when the SCC polymer is at equilibrium at a temperature below Tp, it will not flow and will not change shape permanently (though it may undergo elastic deformation) when subjected to tolerable pressure through the skin. If the equilibrium temperature is between To and Tp, the cooled composition will often more readily undergo elastic deformation.
  • Theological properties of the SCC polymer, at equilibrium under the skin, are also important to the "feel" of the skin over the SCC polymer (i.e. the tactile impression to a person feeling the skin). I have found that SCC polymers having relatively large proportions of soft blocks contribute to an attractive palpability, and I believe that this is because such SCC polymers have a soft, gel-like consistency.
  • an SCC polymer in which the proportion of soft blocks is at least 70%, e.g. at least 85%, preferably at least 84%, e.g. 70 to 98%, or 85 to 97%, or 89 to 93%, e.g. about 91 %.
  • the low glass transition temperature of the soft block enhances the palpability of the skin over the composition.
  • the glass transition temperature of the soft blocks is less than 0°C, particularly less than - 20 0 C, e.g. -32 to -50 0 C.
  • the SCC polymer After the SCC polymer has been placed under the skin, it begins to cool, but there is a delay in reaching equilibrium. Thus, when the polymer has first cooled to below To, and has not reached equilibrium, few or none of the crystallizable groups may have crystallized. This hysteresis effect is valuable in many embodiments of the present invention, because the SCC polymer, after having been placed under the skin, remains for a time in a rheological state which is between the fluid state of the polymer as it was placed under the skin and the equilibrium shape-retaining state.
  • the shape of the polymer can be changed by pressure on the skin over the polymer. That pressure can be provided by the fingers of a practitioner and/or by a practitioner-controlled mechanical instrument which optionally supplies heat to the skin in order to prolong the time during which the polymer can be shaped.
  • this invention can change the appearance of skin in a desired way, e.g. to increase the volume of lips or another part of the body, or to reduce or remove skin blemishes, for example dermal volume loss (DVL), caused by natural aging, disease, or mal-formed skin blemishes such as acne, vermillion border, vermillion, fine lines and wrinkles, folds, furrows and deep wrinkles.
  • DRL dermal volume loss
  • the SCC polymer composition can be delivered to the site in any appropriate way.
  • the composition while it is as a temperature of TL or above (which may be 1 -7 0 C above Tp), is injected subcutaneously through a hypodermic needle or the like having a relatively small size, for example a gauge between 25 and 32.
  • the temperature of the SCC polymer composition when it first contacts the human being must be tolerable to the human being. Since the tissue surrounding the composition will act as a heat sink, the composition has low heat transmissibility, and, in many cases, the fact that the quantity of the composition is small compared to the surrounding tissue, that temperature may be substantially above the temperature that can be tolerated on a continuous basis over a large area. Thus the temperature of the composition when it first contacts the human being can for example be as high as 52°C, though lower temperatures, e.g. less than 48°C, may be preferred.
  • a composition directly under the skin can be melted by applying heat to the outside of the skin, e.g. by means of a thermal wand whose tip is at about 46°C plus or minus 3°C (when touching the skin).
  • the melted composition can then be reshaped by applying pressure to the outside of the skin, e.g. with the thermal wand and/or the practitioner's fingers.
  • some or all of the melted composition can be removed by inserting a hypodermic syringe into the melted composition and applying suction. After removal of the heat, the composition cools back to its body temperature state.
  • the reservoir comprises a hub at the outlet and an electrical heater which substantially surrounds the hub.
  • an electrical heater is placed at the outlet so that, when a needle is attached to the outlet, the heater lies between a fitting on the end of the needle and the parts of the reservoir defining the outlet.
  • the needle comprises a fitting which is fixed to the outlet of the reservoir, and an electrical heater which substantially surrounds the fitting.
  • the needle, and/or the reservoir, and/or a component adjacent to the outlet comprises a magnetically permeable material which can be heated inductively, e.g. by a coil which is part of the device.
  • Suitable magnetically permeable materials include for example nickel-iron alloys and ferrite-filled ceramics.
  • the novel devices are particularly useful for dispensing SCC polymer compositions, but also useful for dispensing other compositions, for example when the human being into which the composition is to be injected derives some benefit, for example improved performance during or after the injection or greater comfort during or after the injection.
  • the piston in the injection device of the invention can be powered manually, hydraulically or pneumatically.
  • Preferred devices are capable of precise volume, flow rate, and temperature control of the composition and/or can operate at high pressures, for example up to and exceeding 5000psi (350 kg per square centimeter), when such pressures are needed to deliver a viscous composition (e.g. an SCC polymer composition as described in (A) above) through a small gauge (for example 23-30 gauge) needle.
  • Flow rates of 0.3 to 3, e.g. 0.5 to 2, cc /min can be used in some cases.
  • the reservoir is preferably constructed from a thermally insulating material, for example, a polymeric material such as polycarbonate or Ultem.
  • the device preferably includes a hub constructed from a thermally conductive material, for example metal, e.g. brass or stainless steel.
  • the hub may be secured to the reservoir, at or near the outlet of the reservoir, or to the end of the needle which is secured to the outlet of the reservoir.
  • the needle is preferably removably attached to the outlet of the reservoir, so that if desired a new needle can be used for successive uses of material from the same reservoir.
  • the needle can include a fitting of substantial thermal mass through which the needle is secured to the outlet.
  • the heating of the composition can be carried out in any way, but is preferably carried out by means of an electrically powered heater.
  • the heater preferably mates geometrically with the hub.
  • the hub can for example be heated to a temperature of 40 to
  • the hub delivers heat to the composition as it passes from the reservoir into the needle.
  • the amount of the composition which is heated at any one time can for example be at most 10%, preferably less than 5%, for example less than 2%, of the total capacity of the reservoir. However, amounts greater than 10% can be heated, for example by heat conducted away from the heater to other parts of the reservoir, e.g. by metal strips extending longitudinally towards the rear end of the reservoir.
  • the heater can for example generate 5-15, e.g. about 10, watts
  • the injection device comprises a hand piece containing a piston in a cylinder that is driven by either hydraulic or pneumatic pressure from a remote pressure source and controller.
  • the drive piston of the hand piece in turn is attached to a piston rod of smaller diameter than the drive piston.
  • This rod mechanically engages and drives a second piston sliding in a thermally insulating, (e.g. a polymeric material such as polycarbonate or Ultem) disposable syringe.
  • the disposable syringe mates removably with the hand piece and is provided with a metal hubbed needle.
  • the needle is designed to be easily replaceable (by simple threading or via a twist-on fitting, e.g. a Leur-Lock fitting).
  • the volume of material delivered by the device is a function of the product of the pressure and the length of time that the pressure is applied by the dispenser, i.e. the person controlling the device.
  • the flow rate of material for a given pressure generally goes up with the temperature of the material ((since high temperatures yield lower viscosities, and, therefore, higher flow rates), and goes down a sharply with a decrease in the needle lumen diameter.
  • the flow rate goes down with an increase in the needle length.
  • the needle lumen diameter is generally fixed for a given needle size and length.
  • the dispenser should balance pressure, time, and temperature of the polymer to achieve optimum performance.
  • the design of the device will consider, among other things, (a) the thermal conductivity of the hub and needle, (b) the diameter and length of the hub, (c) the length and wall thickness of the needle extending beyond the end of the hub, and (d) heater to hub thermal contact efficiency.
  • Preferred features of the invention can optionally include the following.
  • a hydraulically or pneumatically powered hand piece (which may be disposable or non-disposable) which cooperates with an optionally disposable pre-filled reservoir, in order to provide control of pressure on the material in the prefilled reservoir, and which thus allows precise delivery of polymeric implant materials, in particular compositions which are too viscous for convenient manual injection.
  • Remote hydraulic or pneumatic control can be provided by modification of commercially available pressurized dispenser equipment, e.g. an EFD (Nordson Corp. ) 2400 pneumatic or 2800 hydraulic controller.
  • the reservoir can have a shape such that it can conveniently be equipped by the dispenser's fingers.
  • the reservoir is preferably thick-walled so that it will resist high pressures.
  • the reservoir can be optically clear, or can include inspection windows, so that the dispenser can see how much polymer is in the reservoir.
  • the reservoir can include markings to see how much polymer has been dispensed, in total and/or in a particular injection.
  • An electrical heater (which can be disposable or reusable) in combination with a disposable hubbed needle, thus allowing efficient heating of the polymeric composition during delivery and control of the viscosity of the composition.
  • the material and shape of the needle and needle hub material are preferably selected to provide high thermal conductivity while preserving normal needle parameters.
  • Figures 1 -4 show a reservoir 1 having a threaded outlet 1 1 ; a needle 5 having a threaded terminal 51 which can be screwed into the outlet
  • Example 1 In this Example, a hard block oligomer as disclosed in (F) was prepared.
  • the molar ratio of the methacrylate monomer to the mercapto ethanol was 1.33.
  • the reaction mixture was stirred at about 100 RPM and the temperature was maintained at about 60 0 C. All fluorescent lights in the hood and surrounding area were then turned off and the reaction allowed to proceed for approximately 72 hours. When the reaction was complete, the lights were turned back on and a distillation adapter was attached to the reaction vessel. A gentle stream of nitrogen flow was maintained. Most of the toluene was flash-distilled off under partial vacuum and the temperature was then gradually raised to about 60 0 C.
  • Example 2-35 the procedure of Example 1 was followed except that the ratio of the methacrylate monomer to the mercaptoethanol was varied, thus changing the Mn and Mw of the product.
  • the results are summarized in the table below. All the products had a Tp of about 43 0 C.
  • Example 36 In Example 36, the hydroxyl group in the hydroxy-terminated hard block oligomer prepared in Example 1 was converted into a methacrylate derivative, thus preparing another hard block oligomer.
  • Example 3 a block copolymer as disclosed in (C) above was made by polymerizing n-butyl acrylate (referred to below as C4A) on the methacrylate-containing hard block oligomer prepared in Example 36, which is referred to below as FHB (an abbreviation for functionalized hard block).
  • C4A n-butyl acrylate
  • FHB an abbreviation for functionalized hard block
  • Example 38-60 In Examples 38-60, the procedure of Example 37 was followed, except that the quantity of C12SH was changed so that the molar ratio of C4A to C12SH was as stated below. The Tp of all the products was about the same. These Examples show that by adjusting the molar ratio between the C4A and C12SH, block copolymers of various molecular weights can be prepared.
  • Example 38 Example 39 Example 40 Example 41 Example 42 Example 43 Example 44 Example 45 Example 46 Example 47 Example 48 Example 49 Example 50 Example 51 Example 52 Example 53 Example 54 Example 55 Example 56 Example 57 Example 58 Example 59 Example 60
  • This Example shows the preparation of an oligomeric diol corresponding to part of a soft block.
  • a glass reaction flask was added 210Og of methyl acetate, 929.3g (7.251 moles) of C4A, 92.9g (0.714 moles) of hydroxy ethyl methacrylate, 48.23g (0.617 mole) of mercaptoethanol and 7.54g (0.046 mole) of AIBN.
  • the molar ratio of the methacrylate monomer to the mercaptoethanol was 12.90.
  • the reaction mixture was heated to between 58° and 61 0 C for about 70 hours.
  • the mechanical stirrer was maintained at about 100 RPM. All fluorescent lights in the hood and surrounding area were turned off.
  • the purification process was repeated several times until the product was isolated as a water-clear viscous liquid.
  • the product was air dried and, finally, vacuum-dried.
  • the resulting product had am Mn of 1 ,842 and an Mw of 2,565, i.e. a polydispersity of about 1.4.
  • a bioerodable block copolymer having bioerodable phosphate linkages within the soft block and between the soft and hard blocks was prepared using the oligomeric diol prepared in Example 61 and a hydroxy-terminated hard block oligomer prepared according to the procedure of Example 1 but having an Mn of 969. Approximately equimolar amounts of ethyl dichlorophosphate and the oligomeric diol were reacted in the presence of an organic base such as triethylamine or the like. The reaction product is then reacted with the hydroxy-terminated hard block oligomer, thus preparing a block copolymer in which the blocks are linked together through a phosphate linkage.
  • Example 59 The block copolymer produced in Example 59 was heated to about 75°C and drawn into a dozen 1 cc syringes. Any air bubbles trapped in the polymer were allowed to migrate to the surface, after which the filled syringes were sterilized by radiation.
  • a small Yorkshire pig was anesthetized, stabilized and prepped. The breathing and heart rate of the pig were monitored. Several dozen implant sites were marked with a black indelible marker pen. The injection sites were shared between injections of two commercial filler materials (Restylan® and Radiesse®) and the sterile block copolymer of Example 59. Sterile needles (selected from among several 25 to 27 gauge 0.5" needles) were attached to the end of the syringes by means of a Leur-Lock fitting. The tip of the needle was angled at about a 20° angle before it pierced the skin. The needle was inserted approximately 1 1 mm into the tissue. The depth was estimated to be 4 mm below the surface. Using calibrated markings on the barrel, the piston in the syringe was used to inject approximately 0.2 cc of each of the different materials into randomly selected sites.
  • the block copolymer of Example 59 was at a temperature of about 45-48°C when it was injected.
  • Example 59 The block copolymer of Example 59 was rated between the two commercial products.
  • Example 64 Using another anesthetized pig, the procedure of Example 64 was followed using a polymer which was the same as the polymer of example 59 except that the ratio of behenyl methacrylate to octadecyl methacrylate was 55:42 (instead of 62: 38 ) and about 0.1 cc of the polymer was injected.
  • the polymer used in this Example had a Tp of about 38°C and a TL of about 41.2 0 C. Those injected polymer formed small raised lumps about 6mm in diameter. After about 15 minutes, three of these sites were massaged and the lumps flattened out over a broader area.
  • the other sites were cooled to about 25°C either by a stream of cool air or by ice contained in a sterile latex glove. Three of the cooled sites were massaged, but the raised lumps failed to spread out.
  • a thermal wand about the size of a large pen and designed to maintain a 80 sq mm tip at a temperature of 46 to 49°C was applied to the stratum corneum directly above each of the now immobile raised lumps. With the heat and pressure applied by the wand the lump was easily flattened out. This procedure was repeated three more times. The areas that were flattened out were chilled by cool air to set the material and prevent further migration.
  • a removal device was constructed as follows. An empty syringe fitted with a sterile stainless steel 16 gauge needle (0.5" long, and fitted with a nickel plated brass Leur-Lock® hub) was attached to a vacuum line that achieved a negative pressure of 28.5 inches of mercury. The syringe and needle were heated so that the temperature at the tip of the needle was about 45 to 47°C (in air).
  • Example 65 The 5 remaining raised lumps in Example 65 were treated as follows. First, the warm thermal wand was placed directly on top of the lump, thus melting the block copolymer in the lump. Second, the needle of the removal device (without vacuum) was inserted into the center of the raised lump. Third, vacuum was applied to the needle.

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Abstract

Cette invention concerne des compositions qui comprennent des polymères cristallins à chaînes latérales (SCC) et qui sont utiles pour modifier les tissus mous chez les êtres humains et d'autres mammifères. La modification peut produire une amélioration cosmétique et/ou reconstructrice du tissu mou. Les compositions peuvent rester efficaces pendant des périodes de temps prolongées, ou si c'est souhaité, pendant des périodes plus courtes choisies. Les dispositifs d'injection qui sont particulièrement appropriés à la distribution de telles compositions comprennent un réservoir (1) doté d'une sortie (2) à laquelle une aiguille est fixée, un piston (2) qui peut se déplacer au sein du réservoir de manière à pouvoir expulser la composition contenue dans le réservoir vers la sortie, et un élément de chauffage (3) pour chauffer la composition proche de la sortie à une température sensiblement supérieure à la composition relativement éloignée de la sortie.
PCT/US2007/023226 2006-11-03 2007-11-01 Compositions, dispositifs et procédés de modification d'un tissu mou WO2008066657A2 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
US12/114,194 US20090124996A1 (en) 2006-11-03 2008-05-02 Apparatus and methods for injecting high viscosity dermal fillers
PCT/US2008/072310 WO2009021020A1 (fr) 2007-08-08 2008-08-06 Appareil et procédés pour injecter des charges dermiques à haute viscosité
EP08797262A EP2183003A1 (fr) 2007-08-08 2008-08-06 Appareil et procédés pour injecter des charges dermiques à haute viscosité
AU2008283868A AU2008283868B2 (en) 2007-08-08 2008-08-06 Apparatus and methods for injecting high viscosity dermal fillers
US12/187,964 US20090198183A1 (en) 2006-11-03 2008-08-07 Apparatus and methods for injecting dermal fillers
PCT/US2008/072558 WO2009021158A1 (fr) 2007-08-08 2008-08-08 Appareil et procédé d'injection de charges dermiques
US12/477,527 US20090240200A1 (en) 2006-11-03 2009-06-03 Apparatus and methods for injecting high viscosity dermal fillers
US12/871,405 US8343132B2 (en) 2006-11-03 2010-08-30 Apparatus and methods for injecting high viscosity dermal fillers

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US85643006P 2006-11-03 2006-11-03
US60/856,430 2006-11-03
US85775506P 2006-11-08 2006-11-08
US85754606P 2006-11-08 2006-11-08
US60/857,546 2006-11-08
US60/857,755 2006-11-08

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US12/187,964 Continuation-In-Part US20090198183A1 (en) 2006-11-03 2008-08-07 Apparatus and methods for injecting dermal fillers

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US8399007B2 (en) 2006-12-05 2013-03-19 Landec Corporation Method for formulating a controlled-release pharmaceutical formulation
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US8343132B2 (en) 2006-11-03 2013-01-01 Nordson Corporation Apparatus and methods for injecting high viscosity dermal fillers
US8399007B2 (en) 2006-12-05 2013-03-19 Landec Corporation Method for formulating a controlled-release pharmaceutical formulation
US8524259B2 (en) 2006-12-05 2013-09-03 Landec Corporation Systems and methods for delivery of materials
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WO2009073192A3 (fr) * 2007-12-04 2009-10-22 Landec Corporation Systèmes et procédés pour délivrer des substances
US8114883B2 (en) 2007-12-04 2012-02-14 Landec Corporation Polymer formulations for delivery of bioactive materials
WO2010141806A3 (fr) * 2009-06-04 2011-04-28 Landec Corporation Compositions et procédés pour administrer des substances
EP2440192A2 (fr) * 2009-06-11 2012-04-18 Landec Corporation Compositions et procédés pour l'administration de matières
EP2440192A4 (fr) * 2009-06-11 2013-08-28 Landec Corp Compositions et procédés pour l'administration de matières
WO2014139535A1 (fr) * 2013-03-11 2014-09-18 Syddansk Universitet Ensemble d'injection de fluide médical avec chauffage par induction du fluide
WO2014160387A3 (fr) * 2013-03-14 2014-12-18 Pathak Holdings, Llc Compositions, procédés et dispositifs pour l'administration locale de médicament
WO2014160387A2 (fr) * 2013-03-14 2014-10-02 Pathak Holdings, Llc Compositions, procédés et dispositifs pour l'administration locale de médicament
US9345777B2 (en) 2013-03-14 2016-05-24 Pathak Holdings, Llc Methods for local drug delivery by microinjection array
US9789073B2 (en) 2013-03-14 2017-10-17 Pathak Holdings, Llc Compositions, methods and devices for local drug delivery
US10123980B2 (en) 2013-03-14 2018-11-13 Pathak Holdings, Llc Compositions, methods and devices for forming implants from injected liquids
US10543182B2 (en) 2013-03-14 2020-01-28 Pathak Holdings Llc Compositions, methods and devices for forming gel implants from injected liquids
US10624865B2 (en) 2013-03-14 2020-04-21 Pathak Holdings Llc Methods, compositions, and devices for drug/live cell microarrays
US10918611B2 (en) 2013-03-14 2021-02-16 Pathak Holdings Llc Methods for forming implants from injected thermoreversible gels
US11045433B2 (en) 2013-03-14 2021-06-29 Pathak Holdings Llc Method of making an in situ sustained biodegradable drug delivery implant by filling an artificial tissue cavity
US11911352B2 (en) 2013-03-14 2024-02-27 Pathak Holdings Llc Compositions, methods and devices for forming implants from injected liquids
US11969398B2 (en) 2013-03-14 2024-04-30 Pathak Holdings Llc Methods, compositions, and devices for making sustained biodegradable implants in tissue

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WO2008066657A3 (fr) 2008-07-10

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