EP1841406A2 - Methods and formulations - Google Patents

Methods and formulations

Info

Publication number
EP1841406A2
EP1841406A2 EP05854851A EP05854851A EP1841406A2 EP 1841406 A2 EP1841406 A2 EP 1841406A2 EP 05854851 A EP05854851 A EP 05854851A EP 05854851 A EP05854851 A EP 05854851A EP 1841406 A2 EP1841406 A2 EP 1841406A2
Authority
EP
European Patent Office
Prior art keywords
het
formulation
6alkyl
galkyl
compound
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP05854851A
Other languages
German (de)
French (fr)
Other versions
EP1841406A4 (en
Inventor
Simon M. Blake
William Henry Miller
Amyn Sayani
H. Jeffrey Wilkens
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
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.)
Filing date
Publication date
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of EP1841406A2 publication Critical patent/EP1841406A2/en
Publication of EP1841406A4 publication Critical patent/EP1841406A4/en
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids

Definitions

  • This invention relates to methods, topical formulations and methods of using topical formulations for the topical administration of vitronectin receptor antagonists for the prevention of excessive skin scarring.
  • lntegrins are a superfamily of heterodimeric transmembrane glycoproteins that are involved in adhesion as well as communication events. These heterodimeric transmembrane glycoproteins include ⁇ v ⁇ 3 (the vitronectin receptor).
  • the vitronectin receptor ⁇ v ⁇ 3 is expressed on a number of cells, including endothelial, smooth muscle, osteoclast, and tumor cells, and, thus, it has a variety of functions.
  • the OyB 3 receptor expressed on the membrane of osteoclast cells mediates the adhesion of osteoclasts to the bone matrix, a key step in the bone resorption process. Ross, et al., J. Biol.
  • ⁇ v ⁇ 3 receptor expressed on human aortic smooth muscle cells mediates their migration into neointima, a process which can lead to restenosis after percutaneous coronary angioplasty. Brown, et al., Cardiovascular Res., 1994, 28, 1815. Additionally, Okada, et al., Am. J. Pathol., 1996, 149(1), 37 suggest that oc v ⁇ 3 plays a role in vascular integrity and remodeling following focal ischemia within an infarcted area.
  • vitronectin receptor antagonists are useful in inhibiting adhesion formation, in particular, for the treatment of post-surgical adhesions US 2004/0142918.
  • Hypertrophic scars are those that stay within the boundaries of the initial wound while keloid scars spread from the initial wound and invade normal skin.
  • Bayat A. McGrouther DA, Ferguson MWJ 2003 British Medical Journal, 326, 88-92; Brissett AE, Sherris DA 2001 Facial Plastic Surgery, 17 (4), 263-271.
  • Ehrlich HP Desmouliere A, Diegelmann RF, Cohen IK, Compton CC, Garner WL, Kapanci Y 1 Gabbiani G.
  • Hypertrophic scars appear earlier than keloids: ⁇ 4 weeks versus > 3 months to years after trauma. Hypertrophic scars may also slowly regress, though not disappear, while keloids continue to expand. Evidence in the literature indicates that hypertrophic scar formation may be related to the loss of control in the matrix production during the proliferation phase. Lygoe KA, Norman JT, Marshall JF, Lewis MP 2004 Wound Repair and Regeneration, 12, 461 -470. Fibroblast differentiation, survival and collagen production are the key steps involved in this process. Fibroblasts migrate in during the proliferation stage and begin to lay down collagen rich extracellular matrix.
  • integrins including ⁇ v ⁇ 3 and ⁇ v ⁇ 5. It has also been demonstrated that the adhesion of fibroblasts to the extracellular matrix via these integrins is at least partially responsible for triggering the synthesis of the collagen network. The antagonism of this binding would be expected to result in both a decreased fibrosis and a reduction in collagen synthesis and excessive scar formation.
  • Av integrins are also involved in fibroblast differentiation to myofibroblasts. Blockade of ⁇ v ⁇ 3 and ⁇ v ⁇ 5 may also lead to decreased differentiation into myofibroblasts and a blunted response to growth factors such as transforming growth factor b (TGF-b).
  • TGF-b transforming growth factor b
  • the present invention provides methods of using vitronectin receptor antagonists for the prevention of excess scarring of skin, vitronectin receptor antagonist formulations suitable for topical application, and methods of using topical formulations of vitronectin receptor antagonists for the prevention of excess scarring of the skin in a mammal, in particular a human.
  • this invention describes a method of inhibiting excess scar formation on skin comprising the administration of a vitronectin receptor antagonist in a pharmaceutically acceptable formulation to a mammal in need thereof.
  • the mammal to be treated is a human.
  • the methods of this invention comprise the topical administration of a vitronectin antagonist.
  • the methods of this invention utilize a vitronectin receptor antagonist comprising a compound of formula I or II:
  • R is H, Ci. e alkyl, Ar, Het, or C 1-6 alkylaryl
  • R is R , A-Crj-4 alkyl, A-C2-4alkenyl, A-C2-4alkynyl, A-C3-4oxoalkenyl, A-C3-4oxoalkynyl, A-C-
  • A is H, C3-6cycloalkyl, Het or Ar;
  • R 7 is -COR 8 , -COCR'2R 9 , -C(S)R 8 , -S(O) m OR', -S(O)mNR'R", -PO(OR'), -PO(OR')2, -NO2, or tetrazolyi; each R8 independently is -OR 1 , -NR 1 R", -NR'S ⁇ 2R', -NR 1 OR 1 , or -OCR'2CO(O)R';
  • R9 is -OR 1 , -CN, -S(O)rR ⁇ -S(O) m N(R')2, -C(O)R", C(O)N(R')2, or -CO2R';
  • R 1 O is H, halo, -OR11 , -CN, -NR 1 R 11 , -NO2, -CF3, CF3S(O) r , -CO2R 1 , -CON(R')2, A-Co-6alkyl-, A-Ci - ⁇ oxoalkyl-, A-C2-6alkenyI-, A-C2-6alkynyl-, A-Crj-6alkyloxy-, A-Crj- ⁇ alkylamino- or A-Crj-6alkyl-S(0)r-;
  • R 1 1 is R', -C(O)R 1 , -C(O)N(R 1 J 2 , -C(O)OR', -S(O) m R', or -S(O) m N(R 1 ) 2 ;
  • W is -(CH Rg) 3 -U-(CH R9)b-;
  • NRgCRg 21 CRg 2 NRg 1 CRg 2 O 1 OCRg 2 , c ⁇ c Or CRg CRg; G is NRe, S or O;
  • Rg is H 1 C-j.galkyl, Het-Crj-galkyl, C3-7cycloalkyl-Cn-6 a 'kyl or Ar-Crj-6alkyl;
  • R k is R9, -C(O)R9, or -C(O)OR f ;
  • R' is H, C-j _galkyl, Het-C ⁇ -6 a lkyl, C3-7cycIoalkyl-Co-6 a lkyl, Ar- Co-6 a " ⁇ yl, or C-
  • R f is H, Chalky! or Ar-Co-6 a IM
  • R ⁇ is H, C-
  • R ⁇ and R c are independently selected from the group consisting of H, C- ⁇ . ⁇ alkyl, Ar-Co-6a'kyl, Het-Co-6 a lkyl, Cs-ecycloalkyl-Co- ⁇ alkyl, halogen, CF3, OR f , S(O) k R f , COR f , NO 2 , N(R f ) 2j CO(NR f ) 2 , and CH 2 N(R f ) 2 ; or R b and R c are joined together to form a five or six membered aromatic or non-aromatic carbocyclic or heterocyclic ring, unsubstituted or substituted by up to three substituents chosen from the group consisting of halogen, CF3, C- ⁇ alkyl, 0R f , S(O) k R f , COR f , CO 2 R f , OH, NO 2 , N(R f ) 2j CO
  • R' is H, C-i- ⁇ alkyl, Ar-Crj-6alkyl or C 3 -6cycloalkyl-Co-6alkyl;
  • R" is R 1 , -C(O)R 1 or -C(O)OR 1 ;
  • R"' is H, C- ⁇ galkyl, Ar-Co- ⁇ alkyl, Het-Cn-6alkyl, C3-6cycloalkyl-Co_6alkyl, halogen, CF 3 , 0R f , S(O)
  • Ry is H, halo, -0R9, -SR9, -CN, -NR9R k , -NO 2 , -CF 3 , CF 3 S(O) n -CO 2 R9, -C0R9, -CONR9 2 , or C-
  • CN -NR9R", -NO 2 , -CF 3 , R 1 S(O) 1 --, -CO 2 Rg, -CORg, or -CONR9 2 ;
  • a is O 1 1 or 2;
  • b is 0, 1 or 2;
  • k is O, 1 or 2;
  • m is 1 or 2;
  • r is O, 1 or 2;
  • s is 0, 1 or 2;
  • Ai is C or N
  • E is a five- or six-membered heteroaromatic or six-membered aromatic ring optionally substituted by R3 * or R 4* ;
  • X 3 is CR ⁇ 'R ⁇ 1* , NR5 * , S(O) 11 * or O;
  • R' * is H, Ci -6 alkyl, Ar, Het, or C 1-6 alkylaryl;
  • R"* is R' * , -C(O)R 1 * or -C(O)ORs*;
  • R'" * is Cl - ⁇ alkyl, C3-7cycloalkyl-Co-4alkyl or Ar-Co-4alkyl;
  • R1 * is H, C-
  • R2 * is -OR 1* , -NR' * R" * , -NR' * S ⁇ 2R" !* , -NROR' * , -OC(R 1 ⁇ C(O)OR 1* , - OC(R' * )2 ⁇ C(O)-R 1* , -OC(R' * )2C(O)N(R 1* )2, CF3 or COC(R ⁇ ) 2 R 2 ' * ;
  • R2' * is -OR 1* , -CN, -S(O) r *R' * , S(O)2N(R' * )2, -C(O)R 1* , C(0)N(R' * )2 or - CO2R 1* ;
  • R5 * and PS' * are independently H, Ci -galkyl, C3-7cycloalkyl-Co-4alkyl or Ar- Co-4alkyl;
  • R6 * is W-(C(R 1* )2)q * -Z * -(CR' * Ri0 * ) r *-U * -(C(R 1* )2)s*-V * - or W' * -(C(R' * )2)q*- U * -(C(R' * ) 2 ) S * -;
  • R3 * , R4 * and R7 * are independently H, halo, -0R12 * , -SR12 * , -CN, -
  • R8 * is R 1 *, C(O)R 1 *, CN, NO2, S ⁇ 2R'*or C(O)OR5 * ;
  • R9 * is R 1* , -CF3, -SR 1* , or -OR 1* ;
  • R1O * is H, C-
  • R12 * is R 1* , -C(O)R 1* , -C(O)N(R' * )2, -C(O)OR5 * , -S(0)m*R' * or S(O)2N(R'*)2;
  • R14 * is H, C3-6cycloalkyl, Het or Ar;
  • Q* is NR' * , 0 or S
  • Ra * is H, C-
  • Rb * and Rc * are independently selected from the group consisting of H, Ci- ⁇ a'kyl.
  • Ar-Co-6 al M. Het-Co-6alkyl, or Cs- ⁇ cycloalkyl-Co- ⁇ alkyl, halogen, OR1 * , SR1 * , COR1 * , OH, NO 2 , N(R1 * ) 2 , CO(NR1 * ) 2> CH 2 N(R1 * ) 2J or Rb * and Rc * are joined together to form a five or six membered aromatic non-aromatic ring, optionally substituted by halogen, Ci ⁇ alkyl, OR1 * .
  • SR1 * , COR1 * , OH 1 NO 2 , N(R1 * ) 2 , CO(NRi * ) 2J CH 2 N(Ri * ) 2 , CN 1 or R"*R' * NC( NR' * )-;
  • Y* is absent, S or O;
  • Z* is (CH 2 )t*, Het, Ar or C3-7cycloalkyl
  • M* is 1 or 2
  • N* is 0, 1 , 2, or 3; q* is 0, 1 , 2, or 3; r * is 0, 1 or 2; s* is 0, 1 or 2; t* is 0, 1 or 2; u* is 0, 1 or 2; v * is 0 or 1 ; and w* is 0 or 1 ; or or a pharmaceutically acceptable salt or solvate thereof.
  • the compound of formula I is Ia
  • R is H, Ci -6 alkyl, Ar, Het, Ci -6 alkylaryl; or a pharmaceutically acceptable salt or solvate thereof.
  • the compound of formula Ia is Ia*
  • R is H, C 1-6 alkyl, Ar, Het, C 1-6 alkylaryl; or a pharmaceutically acceptable salt or solvate thereof.
  • the compound of formula Na is Ha *
  • this invention describes a method of inhibiting excess hypertrophic scar formation on skin comprising the topical administration of a pharmaceutically acceptable topical formulation comprising a carrier and a compound of formula I, II, Ia, Ha, Ia * , or Ha*, or a pharmaceutically acceptable salt or solvate thereof.
  • this invention describes a formulation suitable for the topical administration of a compound of formula I or II,
  • R is H, Ci. 6 alkyl, Ar, Het, or C t . 6 alkylaryl;
  • R is R , or A-Crj-4 alkyl-, A-C2-4alkenyl-, A-C2-4alkynyl-, A-C3-4 ⁇ xoalkenyl-, A-C3-4oxoalkynyl-, A-Ci_4aminoalkyl-, A-C3_4aminoalkenyl-, A-C3_4aminoalkynyl-, optionally substituted by any accessible combination of one or more of R 1 ° or R 7 ;
  • A is H, C3-6cycloalkyl, Het or Ar;
  • R7 is -COR 8 , -COCR'2R 9 , -C(S)R 8 , -S(O)mOR', -S(OJmNR 1 R", -PO(OR 1 ), -P0(0R')2, -N ⁇ 2, or tetrazolyl; each R 8 independently is -OR 1 , -NR 1 R", -NR'SO2R', -NR 1 OR 1 , or -OCR'2CO(O)R";
  • R9 is -OR 1 , -CN, -S(O) r R', -S(O) n N(R ⁇ , -C(O)R 1 , C(O)N(R') 2 , Or -CO 2 R 1 ;
  • R 10 is H, halo, -OR 1 1 , -CN, -NR 1 R 1 1 , -NO 2 , -CF3, CF3S(0) r , -CO 2 R', -C0N(R')2, A-Co-6alkyl-, A-Ci _6oxoalkyl-, A-C 2 -6alkenyl-, A-C 2 -6alkynyl-, A-Co-6alkyloxy-, A-Co-6 a lkylamino- or A-Crj-6 a
  • R 1 1 is R 1 , -C(O)R 1 , -C(0)N(R')2, -C(O)OR", -S(O) n R', or -S(0)mN(R') 2 ;
  • W is -(CHRg)a-U-(CHR9)b-;
  • G is NR e , S or O;
  • RS is H, C-] _@alky[, Het-Co-galkyl, C 3 -7cycloalkyl-Co-6alkyl or Ar-Crj-6alkyl;
  • R k is RS, -C(O)RQ, or -C(O)OR f ;
  • R' is H, C-
  • Rf is H, C-] . ⁇ alkyl or Ar-Co- ⁇ alkyl;
  • R e is H 1 Ci- ⁇ alkyl, Ar-Co- ⁇ alkyl, Het-Co- ⁇ alkyl, C3-7cycloalkyl-Co-6alkyI > or
  • Rb and R c are independently selected from the group consisting of H, C- ] . galkyl, Ar-Co-6alkyl, Het-Crj-6alkyl, Cs- ⁇ cycloalkyl-Co-ealkyl, halogen, CF3, OR*,
  • Q 1 , Q 2 , Q 3 and Q 4 are independently N or C-RY, provided that no more than one of Q 1 , Q 2 , Q 3 and Q 4 is N;
  • R' is H, Ci-6alkyl, Ar-Crj- ⁇ alkyl or C3-6cycloalkyl-Cn,-6alkyl;
  • R" is R 1 , -C(O)R 1 or -C(O)OR 1 ;
  • R'" is H, Chalky], Ar-Co- ⁇ alkyl, Het-Co- ⁇ alkyl, C3-6cycloalkyl-Cn . -6alkyl, halogen, CF 3 , OR f , S(O) k R f , C0R f , NO 2 , N(R f ) 2j CO(NRf) 2 , or CH 2 N(Rf) 2 ;
  • Ry is H, halo, -ORS, -SRS, -CN, -NRSRk, _ N o 2 , -CF 3 , CF 3 S(O) n -CO 2 RS,
  • is C or N
  • E is a five- or six-membered heteroaromatic or six-membered aromatic ring unsubstituted or substituted by R3 * or R4 * ;
  • X3 is CR5 * R5' * , NR5 * , S(O) U * or O;
  • R' * is H, C 1-6 alkyl, Ar, Het, or C 1- ⁇ alkylaryl;
  • R"* is R 1 *, -C(O)R 1 * or-C(O)OR5*;
  • R'"* is Ci-6alkyl, C3-7cycloalkyl-Co-4alkyl or Ar-Cn-4alkyl;
  • R1 * is H, Ci-6alkyl, or Ar-Co-4alkyl;
  • R2 * is -OR 1* , -NR ⁇ R" * , -NR' * S ⁇ 2R'"*, -NROR 1* , -OC(R 1 ⁇ C(O)OR' * , -
  • R2' * is -OR 1* , -CN, -S(O) r *R' * , S(O)2N(R' * )2, -C(O)R 1* , C(O)N(R' * ) 2 or - CO2R 1* ;
  • R5 * and R5' * are independently H, Ci _6alkyl, C3-7cycloalkyl-Co-4alkyl or Ar- Cf>4alkyl;
  • R6 * is W*-(C(R'*)2)q*-Z*-(CR"*RiO * ) r * j -U*-(C(R'*)2)s*-V*-, or W' * -(C(R'*)2)q*- U * -(C(R 1* )2)s * -;
  • R3 * , R4 * and R7 * are independently H, halo, -OR12 * , -SR12 * , -CN, -
  • R8 * is R 1 *, C(O)R 1 *, CN, NO 2 , SO 2 R' * or C(O)OR5 * ;
  • R9 * is R 1 *, -CF3, -SR' * , or -OR 1* ;
  • R1O * is H, Ci-4alkyl or -NR'*R"*;
  • R12 * is R 1* , -C(O)R' * , -C(O)N(R' * )2, -C(O)OR5 * , -S(0) m *R' * or S(O) 2 N(R' * ) 2 ;
  • R14 * is H, C3-6cycloalkyl, Het or Ar;
  • R15 * is H, Cl -1 oalkyl, C3-7cycloalkyl-Co-8all ⁇ yl or Ar-Co-8alkyl;
  • Q * is NR 1 *, O or S
  • R a* is H, Ci- ⁇ alkyl, Ar-Co-6 a
  • Rb * and Rc * are independently selected from H, C-
  • N * is O, 1 , 2, or 3; q* is ⁇ , 1 , 2, or 3; r * is 0, 1 or 2; s* is O, 1 or 2; t* is 0, 1 or 2; u * is 0, 1 or 2; v* is 0 or 1 ; and w * is 0 or 1 ; or a pharmaceutically acceptable salt or solvate thereof, wherein the formulation comprises from about 0.01 % to 50% w/w of the compound of formula I or Il and from about 0.5% to 99% of one or more penetration enhancers.
  • the compound of formula I is Ia,
  • R is H, d ⁇ alkyl, Ar, Het, C ⁇ salkylaryl; or a pharmaceutically acceptable salt or solvate thereof, and the compound of formula Il is Ha,
  • R 2* is H, C 1-6 alkyl, Ar, Het, C 1-6 alkylaryl; or a pharmaceutically acceptable salt or solvate thereof.
  • the compound of formula Ia is 1a*,
  • this invention describes a formulation comprising a compound of formula I, II, Ia, Ha, Ia*, or Ha * , wherein the compound of formula I, II, Ia, Ha, Ia * , or Ha*, comprises from about O.01 % to 10% w/w of the formulation.
  • this invention describes a formulation suitable for topical administration comprising a compound of formula I, II, Ia, Ha, Ia*, or Ha* and further comprising one or more penetration enhancers wherein the penetration enhancer or enhancers comprise from about 0.5% to 40% w/w of the formulation. In some embodiments, this invention describes a formulation suitable for topical administration comprising a compound of formula I, II, Ia, Ha, Ia * , or Ha * and further comprising one or more penetration enhancers wherein the penetration enhancer or enhancers comprise from about 0.5% to 25% w/w of the formulation.
  • the formulations of this invention comprise a penetration enhancer selected from a group consisting of propylene glycol, benzyl alcohol, polyethylene glycols, dimethyl isosorbide, diethylene glycol monomethyl ether, macrogol 2 stearyl ethers, polyoxyl stearyl ethers, polyoxyl lauryl ethers, polyoxyl cetyl ethers, laurocapram, and caprylocaproyl macrogol-8 glycerides, or combinations thereof.
  • a penetration enhancer selected from a group consisting of propylene glycol, benzyl alcohol, polyethylene glycols, dimethyl isosorbide, diethylene glycol monomethyl ether, macrogol 2 stearyl ethers, polyoxyl stearyl ethers, polyoxyl lauryl ethers, polyoxyl cetyl ethers, laurocapram, and caprylocaproyl macrogol-8 glycerides, or combinations thereof.
  • formulations of this invention comprise a penetration enhancer or enhancers wherein said penetration enhancer or enhancers comprises propylene glycol. In some embodiments, formulations of this invention comprises a penetration enhancer or enhancers wherein said penetration enhancer or enhancers comprises at least one surfactant.
  • the formulations of this invention have a pH of greater than about 7. In some embodiments, the formulations of this invention have a pH of greater than 8. In some embodiments, this invention describes a formulation having a pH of from about 8.5 to 9.5.
  • the formulations of this invention comprise from about 1 % to 45% w/w of a buffer having a pH in the range of from 8 to 11. In some embodiments, the formulations of this invention comprise from about
  • the formulations of this invention comprise from about 4% to 12% w/w of one or more emollients. In some embodiments, the formulations of this invention comprise from about
  • the formulations of this invention comprise from about 0.001 % to 2% of one or more antioxidants.
  • the formulations of this invention comprise from about 0.05% to 5% of a compound of formula I, II, Ia, Ha, Ia*, or Ha*; from about 40% to 60% w/w of one or more waxes, ointments, or bases, or combinations thereof; from about 6% to 10% w/w of one or more emollients; from about 1.0% to 25% of one or more penetration enhancers; from about 0.01% to 1 % of one or more antioxidants; and from about 5% to 35% w/w of a pH 9-11 buffer. In some embodiments, the formulations of this invention comprise from about
  • the formulations of this invention comprise from about 0.1 % to 2% w/w of the compound of formula I, II, Ia, lla, Ia * , or Ha * ; from about 50% to 60% w/w of one or more waxes, ointments, or bases, or combinations thereof; from about 7% to 9% w/w of one or more emollients; from about 10.0% to 18% of one or more penetration enhancers; from about 0.01 % to 0.2% of one or more antioxidants; and from about 20% to 28% w/w of a pH 9.5-10.5 buffer.
  • the formulations of this invention comprise from about 0.1 -1.0% of the compound of formula I, II, Ia, lla, Ia*, or lla * ,; from about 45% to 55% petrolatum; from about 6% to 10% mineral oil; from about 3% to 8% polyoxyl stearyl ether; from about 0.01 % to 0.1 % butylated hydroxyanisole; and from about 20% to 28% w/w borate buffer with a pH about 10.
  • this invention describes a method of preventing excessive scarring comprising the topical administration of a formulation of this invention, wherein said administration is to a mammal's skin, wherein said skin has been cut, split, torn, or otherwise injured in such a way that excessive scarring upon healing might result.
  • this invention describes a method of preventing excessive scarring comprising the topical administration of a formulation of this invention, wherein said administration is to a human's skin, wherein said skin has been cut, split, torn, or otherwise injured in such a way that excessive scarring upon healing might result.
  • the methods of his invention comprise the repeated administration of a topical formula of this invention.
  • C- ⁇ .4 alkyl as applied herein means an optionally substituted alkyl group of 1 to 4 carbon atoms, and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl.
  • C- ⁇ alkyl additionally includes pentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof.
  • Cn-4alkyl and Co-6 al M additionally indicates that no alkyl group need be present (e.g., that a covalent bond is present).
  • C 2 . 6 alkenyl as applied herein means an alkyl group of 2 to 6 carbons wherein a carbon-carbon single bond is replaced by a carbon-carbon double bond.
  • C 2-5 alkenyl includes ethylene, 1-propene, 2-propene, 1-butene, 2-butene, isobutene and the several isomeric pentenes and hexenes. Both cis and trans isomers are included.
  • C 2 . 6 alkynyl means an alkyl; group of 2 to 6 carbons wherein one carbon- carbon single bond is replaced by a carbon-carbon triple bond.
  • C 2 .6alkynyl includes acetylene, 1 -propyne, 2-propyne, 1 -butyne, 2-butyne, 3-butyne and the isomers of pentyne and hexyne.
  • Ci. 4 oxoalkyl refers to an alkyl group of up to four carbons wherein a CH 2 group is replaced by a C(O), or carbonyl group. Substituted formyl, acetyl, 1- propanal, 2-propanone, 3-propanal, 2-butanone, 3-butanone, 1- and 4-butanal groups are representative.
  • d. 6 oxoalkyl includes additionally the higher analogues and isomers of five and six carbons substituted by a carbonyl group.
  • C 3 . ⁇ oxoalkenyl and C 3 - 6 oxoalkynyl refers to a C 3 . 6 alkenyl or C 3 .
  • C 3 . 4 oxoalkenyl includes 1 -oxo-2-propenyl, 3-oxo-1- propenyl, 2-oxo-3-butenyl and the like.
  • _4alkyl or C- ⁇ .Q alkyl, C2-6 alkenyl, C2-6 alkynyl, C1.4 oxoalkyl, C- ⁇ .Q oxoalkyl, C 3-4 oxoalkenyl, C3-6 oxoalkenyl and C 3 . 6 oxoalkynyl may be optionally substituted with the group R x , which may be on any carbon atom that results in a stable structure and is available by conventional synthetic techniques.
  • Suitable groups for R x are C- j ⁇ alkyl, OR 1 , SR", C- ⁇ alkylsulfonyl, C-j ⁇ alkylsulfoxyl, -CN,
  • R14*-CI -6 alkyl refers to a Ci -6 alkyl group wherein in any position a carbon- hydrogen bond is replaced by a carbon-Ri4 * bond.
  • Ri4 * -C2-6 alkenyl and R14 * -C 2 - 6 alkynyl have a similar meaning with respect to C2-6 alkenyl and C2-6 alkynyl.
  • Halogen or halo means F, Cl, Br, and I.
  • Ar, or aryl as applied herein, means phenyl or naphthyl, or phenyl or naphthyl substituted by one to three substituents, such as those defined above for alkyl, especially C ⁇ alkyl, C- ⁇ alkoxy, C ⁇ alkylthio, CF 3 , NH2, OH, F, Cl, Br or I.
  • Het, or heterocycle indicates an optionally substituted five or six membered monocyclic ring, or a nine or ten-membered bicyclic ring containing one to three heteroatoms chosen from the group of nitrogen, oxygen and sulfur, which are stable and available by conventional chemical synthesis.
  • heterocycles are benzofuryl, benzimidazole, benzopyran, benzothiophene, furan, imidazole, indoline, morpholine, piperidine, piperazine, pyrrole, pyrrolidine, tetrahydropyridine, pyridine, thiazole, thiophene, quinoline, isoquinoline, and tetra- and perhydro- quinoline and isoquinoline. Any accessible combination of up to three substituents on the Het ring, such as those defined above for alkyl that are available by chemical synthesis and are stable are within the scope of this invention.
  • C3-7cycloalkyl refers to an optionally substituted carbocyclic system of three to seven carbon atoms, which may contain up to two unsaturated carbon-carbon bonds.
  • Typical of C3-7cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl and cycloheptyl. Any combination of up to three substituents, such as those defined above for alkyl, on the cycloalkyl ring that is available by conventional chemical synthesis and is stable, is within the scope of this invention.
  • ⁇ indicates a nitrogen heterocycle, which may be a saturated or unsaturated stable five-, six- or seven-membered monocyclic ring, or a seven- to ten-membered bicyclic ring containing up to three nitrogen atoms or containing one nitrogen atom and a heteroatom chosen from oxygen and sulfur, and which may be substituted on any atom that results in a stable structure.
  • the nitrogen atom in such ring may be substituted so as to result in a quaternary nitrogen.
  • the nitrogen heterocycle may be substituted in any stable position by H, Ci-4alkoxy, F,
  • ⁇ are pyrroline, pyrrolidine, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyraxolidine, piperidine, piperazine, morpholine, pyridine, pyridinium, tetrahydropyridine,tetrahydro- and hexahydro-azepine, quinuclidine, quinuclidinium, quinoline, isoquinoline, and tetra- and perhydro- quinoline and isoquinoline.
  • ⁇ may be pyridyl, pyrolidinyl, piperidinyl, piperazinyl, azetidinyl, quinuclidinyl or tetrahydropyridinyl.
  • ⁇ is preferably 4-pyridyl, 4-(2-amino-pyridyl), 4-tetrahydropyridyl, 4-piperidinyl or 4- piperazinyl.
  • Rb and R c When Rb and R c are joined together to form a five- or six-membered aromatic or non-aromatic carbocyclic or heterocyclic ring fused to the ring to which R ⁇ and R c are attached, the ring formed will generally be a five- or six-membered heterocycle selected from those listed above for Het, or will be a phenyl, cyclohexyl or cyclopentyl ring.
  • t-Bu refers to the tertiary butyl radical
  • Boc refers to the t-butyloxycarbonyl radical
  • Fmoc refers to the fluorenylmethoxycarbonyl radical
  • Ph refers to the phenyl radical
  • Cbz refers to the benzyloxycarbonyl radical
  • Bn refers to the benzyl radical
  • Me refers to methyl
  • Et refers to ethyl
  • Ac refers to acetyl
  • AIk refers to C ⁇ _4alkyl
  • Nph refers to 1 - or
  • 2-naphthyl and cHex refers to cyclohexyl. Tet refers to 5-tetrazolyl.
  • vitronectin receptor antagonists for the prevention of scarring and can be administered via any method deemed appropriate to accomplish that purpose. It is preferred that the methods of this invention utilize a topical administration of a vitronectin receptor antagonist.
  • the methods of this invention may be used to treat or prevent scarring or excess scar formation. By prevention of excess scarring, it is meant that the methods of this invention are preferably utilized before a scar has healed entirely.
  • Some non-limiting examples of vitronectin receptor antagonists useful for the purposes of this invention are described in include those described in the following: PCT Application No. PCT/US95/08306, published as WO 96/00730; PCT Application No.
  • PCT/US95/08146 published as WO 96/00574; PCT Application No. PCT/US96/11108, published as WO97/01540; PCT Application No. PCT/US96/20748, published as WO 97/24119; PCT Application No. PCT/US96/20744, published as WO WO97/24122; PCT Application No. PCT/US96/20327, published as WO 97/24124; PCT Application
  • this invention provides a formulation comprising a compound of formula I, II, Ia, Ha, Ia * , or Ha* which is suitable for topical administration.
  • the compound of formula I, II, Ia, Ha, Ia*, or Ha * is present in from about 0.01 % to 99% w/w of the formulation, or from about 0.01% to 50%, or from about 0.01 to 10%, or from about 0.05% to 5%, or from about 0.1 % to 2%, or from about 0.1 % to 1 %, or about 2%, or about 1 %, or about 0.5%, or about 0.1 %.
  • this invention describes a compound of formula I, II, Ia, Ha, Ia * , or Ha* which is suitable for topical administration wherein said formulation includes at least one penetration enhancer.
  • a penetration enhancer is any substance which facilitates the absorption of a substance through the skin and for purposes of this invention, water is excluded from the definition of a penetration enhancer.
  • a penetration enhancer is any substance whose primary purpose is as a wax, ointment, base or emollient. Penetration enhancers may sometimes serve as drug substance solubilizers.
  • low molecular weight alcohols such as methanol, ethanol, 2-propanol, propylene glycol, and the like. Higher molecular weight alcohols may also be sometimes used, such as polyethylene glycols (PEG), and the like.
  • Alkyl methyl sulfoxides such as dimethyl sulfoxide (DMSO), decylmethyl sulfoxide or tetradecylmethyl sulfoxide and the like, may also be useful.
  • Pyrrolidinones such as 2-pyrrolidinone, N-methyl-2- pyrrolidinone or N-(2-Hydroxyethyl)pyrrolidone, and the like, might also be useful.
  • Laurocapram might also be useful as well as additional miscellaneous solvents such as acetone, dimethyl acetamide, dimethyl formamide, glycol ethers (such as diethylene glycol monomethyl ether (Transcutol ® ), caprylocaproyl macrogol-8 glycerides (Labrasol ® ), or tetrahydrofurfuryl alcohol, and the like, might also be useful for the formulations and methods of this invention.
  • Surfactants might also serve as penetration enhancers.
  • Surfactants include amphiphilic molecules such as anionic surfactants, cationic surfactants, amphoteric surfactants, nonionic surfactants (such as polyoxyethylene alkyl ethers including macrogol 2 stearyl ethers, polyoxyl stearyl ethers, polyoxyl lauryl ethers, polyoxyl cetyl ethers) and fatty acids or alcohols (such as benzyl alcohol).
  • the penetration enhancer or enhancers may be present in any amount deemed to be effective for the particular formulation and indication being studied.
  • the penetration enhancer or enhancers is present in from .5% to 99%, in some embodiments .5% to 40%, in some embodiments .5% to 25%, in some embodiments 1% to 25%, in some embodiments 4% to 18%, in some embodiments 10% to 18%, in some embodiments 10%, or 11%, or 12%, or 13%, or 14%, or 15%, or 16%.
  • the formulations of this invention include one or more waxes, ointments, or bases, or a combination thereof.
  • ointments, bases or waxes of this invention typically include semisolid substances which serve as vehicles for the delivery of the drug substance while not undergoing significant absorption itself. Ideally, these substances are compatible with the skin, possess good stability, are smooth and readily applied (pliable), are not irritating or sensitizing, and are capable of delivering the drug substance.
  • Substances serving as waxes, oils, or ointments in this invention are preferably not highly absorbed by the skin.
  • Useful bases include petrolatums such as white petroleum jelly, yellow petroleum jelly, polyethylene glycol, and mineral jelly, and the like.
  • the wax, ointment, or base, or combination thereof is present in from 0.5% to 99%, in some embodiments from 25% to 75%, in some embodiments from 40% to 60%, in some embodiments from 50% to 60%, in some embodiments 45% to 55%, in some embodiments about 50%, or about 51 %, or about 52%, or about 53%, or about 54%, or about 55%, or about 56%, or about 57%, or about 58%.
  • the formulations of this invention, and methods of treatment using the formulations of this invention include a pH-buffered solution.
  • the pH-buffered solution is present in from about 0.5% to 65% w/w of the formulation, in some embodiments from about 1 % to 45% w/w; or from about 5% to 35% w/w; or from about 10% to 30% w/w; or from about 20% to 28% w/w; or about 24%.
  • the pH buffer of this invention facilitates the transport of the compounds of this invention, especially where said compounds are capable of forming zwitterionic salts.
  • the buffer can serve to facilitate the deprotonation of said salt and thus reduce the zwitterionic character of the drug substance.
  • the pH of the buffer selected as well as the chemical make up of the buffer are to be determined primarily by the contents of the formulation, including the drug used in the formulation.
  • the buffers used in the formulations of this invention have a pH of about 8 to 11 ; or about 9 to 11 ; or about 9.5 to 10.5; or about 9.6 to 10.4, or about 10.
  • the pH buffers of this invention consist of a weak acid and its conjugate base.
  • buffers of this invention include (H 3 BO 3 Z[B(OH) 4 ] " ); (HCO 3 VCO 3 2 -); (HSO 4 VSO 4 2 -); (H 2 PO 4 V HPO 4 2" ); citrate/citric acid; and tartrate/tartaric acid.
  • the pH of the topical formulations of this invention may be controlled by the inclusion of an acid or base buffer, or a pharmaceutically acceptable acid or base in a non-buffered embodiment.
  • the base or acid used maybe organic or inorganic.
  • the formulations of this invention have pHs of >7, or >8, or about from 8.5 to about 9.5, or from about 8 to about 9, or from about 7.5 to 8.5, or from about 7 to about 9, or from about 8.5 to 8.7.
  • Such acids can be used to bring the pH down into a desired range of less than 7, or less than 6, or from about 5 to 7, or from about 4 to 6, or from about 3 to 6, or about 4.
  • the formulations of this invention include one or more emollients.
  • Emollients are typically bland, fatty or oleaginous substances which helps to both soften the skin as well as protect the skin from various air born contaminants while the skin heals.
  • emollients useful for the purposes of this invention include cetostearyl alcohol, sesame oil, lanolin, mineral oil, coconut oil, sulfated castor oil, petrolatum, corn oil, isopropyl palmitate, cetyl esters wax, lecithin, cholesterol, glycerol, glyceryl monostearate, castor oil, isopropyl myristate, mineral oil, petrolatum (white or yellow), petrolatum alcohols, cold cream, cotton seed oil, hydrophilic ointment, rose water ointment, and theobroma oil.
  • the emollient or emollients may be present in any amount deemed beneficial to the particular formulation contemplated.
  • an emollient or emollients maybe present in from about 0.1 % to 65% w/w of the formulation, or from about 0.5% to 45%, or from about 2% to 25%, or from about 4% to 15%, or from about 4% to 12%, or from about 6% to 10%, or from about 7% to 9%, or from about 6%, or about 7%, or about 8%, or about 9% or about 10%.
  • the formulations of this invention include one or more antioxidants.
  • an antioxidant is any substance that can prevent, hinder, slow or otherwise inhibit the oxidative deterioration of any component of the formulation.
  • antioxidants contemplated for use in this invention include ascorbic acid, ascorbic acid esters, butylated hydroxyanisole, butylated hydroxytoluene, sodium or potassium metabisulfite, sodium or potassium bisulfite, fumaric acid, malic acid, alpha tocopherol, or propyl gallate.
  • the formulations of this invention contain from about 0.001% to 5% antioxidant, or from about 0.001% to 4%, or from about 0.001 % to 3%, or from about 0.001 % to 2%, or from about 0.01 % to 1 %, or from about 0.01 % to 0.5%, or from about 0.01 % to 0.4%, or from about 0.01 % to 0.3%, or from 0.01 % to 0.2%; or from about 0.1 % to 1%, or from about 0.1 % to 0.5%, or from about 0.1% to 0.4%, or from about 0.1% to 0.3%, or from about 0.1% to 0.2%, or about 0.1%, or about 0.2%, or about 0.3%, or about 0.4%, or about 0.5%.
  • the formulations of this invention may include an antimicrobial agent.
  • antimicrobial agents contemplated for the purposes of this invention are benzoic acids or benzoate salts, editic acid, phenol, sorbic acid, benzyl alcohol, isopropyl alcohol, benzethonium chloride, propylparaben, imidurea, propionate salts, bronopol, butylparaben, cetrimide, chlorhexidine, phenylmercuric nitrate, potassium sorbate, propylene glycol, chlorbutanol, chlorocresol, cresol, ethylparaben, glycerol, methylparaben, phenoxyethanol, phenethyl alcohol, phenylmercuric acetate, phenylmercuric borate, and thimersol.
  • formulations of this invention are comprised of various possible combinations of those ingredients or excipients listed above. Accordingly, formulations may comprise combinations of those ingredients in the described ranges or the formulation may comprise subcombinations of ingredients or excipients listed above wherein not every category of excipient or ingredient is represented in every formulation.
  • Emollient(s) 6% to 10%
  • Antioxidant(s) 0.01 % to 1 %
  • Emollient(s) 6% to 10%
  • Antioxidant(s) 0.01% to 0.5%
  • Antioxidant(s) 0.01% to 0.2%
  • Emollient(s) 4% to 12%
  • Antioxidant(s) 0.001% to 2%
  • Emollient(s) 6% to 10%
  • Antioxidant(s) 0.01 % to 1%
  • Emollient(s) 6% to 10%
  • Antioxidant(s) 0.01% to 0.5%
  • Antioxidant(s) 0.01% to 0.2%
  • the methods of this invention are directed to the administration of vitronectin receptor antagonists which are useful for the prevention of excessive scarring of skin.
  • the formulations of this invention are useful for the treatment of normal, hypertrophic or keloid scarring.
  • the formulations of this invention maybe used to prevent hypertrophic or normal scarring.
  • the formulations of this invention maybe used as a method of treating hypertrophic scarring.
  • the methods of this invention relate to the prevention of scarring of the skin which occurs after an injury or insult to the skin, most often in the form of a cut or splitting in the skin which upon healing, might form a normal scar, a hypertrophic scar or a keloid scar.
  • the treatment methods of this invention comprise the administration of a vitronectin receptor antagonist, wherein said administration may be oral, parenteral, inhaled, topically, or through a mucous membrane via insert or suppository.
  • the compositions of vitronectin receptor antagonists useful for the purposes of this invention may be formulated as solutions or lyophilized powders for parenteral administration. Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use.
  • Liquid formulations useful for the methods of this invention may be buffered or non-buffered. Some examples of suitable diluents are normal isotonic saline solutions, standard 5% dextrose in water or buffered sodium or ammonium acetate solution.
  • formulations are especially suitable for parenteral administration, they may also be used in oral administrations, or contained in a metered dose inhaler or a nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidinone, gelatin, mannitol, sodium chloride or sodium citrate.
  • these compounds may be encapsulated, tableted or prepared in an emulsion or syrup for oral administration.
  • Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition.
  • Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, pectin, acacia, agar or gelatin.
  • Liquid carriers include syrup, peanut oil, olive oil, saline and water.
  • the carrier may include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the amount of solid carrier may vary according to the need, but typically will include between 10 mg and 750 mg per dosage unit.
  • compositions can be made according to conventional techniques such as milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms. If a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Such a liquid formulation may be administered directly p.o. or filled in a soft gelatin capsule.
  • Rectal or vaginal administration may also be used to perform the methods of this invention and accordingly, vitronectin receptor antagonists may be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded or formed into a suppository.
  • excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols
  • the typical dosage When a vitronectin receptor antagonist is administered orally, the typical dosage will be between 0.1 mg/kg and 50 mg/kg, depending upon the particular antagonist used as well as the particulars of the patient's condition and presentation. Preferably, the oral dosage will be between 0.5 mg/kg and 25 mg/kg.
  • an intravenous infusion of the vitronectin receptor antagonist in an aqueous solution may be preferable.
  • the vitronectin receptor antagonist may be conveniently coadministered, if desired, with other substances via the IV.
  • a dose via IV will be between 0.1 mg/kg and 20 mg/kg and may be administered as needed.
  • the vitronectin receptor antagonist may be administered via a depot formulation wherein the substance is injected or placed into a subdermal depot and allowed to release over a period of time. Vitronectin receptor antagonists may also be injected intradermally which is accomplished by injection of a vitronectin antagonist near the wound site. The injections may be administered once or as part of a series of injections depending on what the situation dictates. In some embodiments, this invention describes the topical application of a vitronectin receptor antagonist to injured skin in order to prevent excess scarring. In some embodiments, the formulation of this invention may be topically applied once and in some embodiments, the formulation will need to be applied repeatedly.
  • the treatment regimen maybe comprised of formulations of this invention administered prior to, or coadministered or administered subsequently to therapy with other known or possible scar formation palliatives including surgery, pressure, corticosteroids, radiation, silicone, laser, cryotherapy, formalin, pepsin, HCI, oil of creosote, penacillamine, colchicines, 5-fluorouracil, bleomycin and interferon.
  • the formulations of this invention may be administered in any form suitable for a topical administration.
  • a formulation of this invention may be prepared as, and administered, for example, a cream, ointment, solution, gel, salve, emulsion, lotion, suspension or a semi-solid.
  • the methods and formulations of this invention may also be administered with a wound healing device.
  • a wound healing device For example, a bandage, wrap, cast and the like, may be impregnated with a vitronectin receptor antagonist and be placed over the wound site, and the device changed as needed.
  • Cream formulations are generally prepared using an emulsification process whereby the aqueous and oil phases are first prepared in separate vessels.
  • Example formulation #1 (Table 15), #2 (Table 16), or #3 (Table 17) in this invention were manufactured by first preparing the aqueous phase.
  • the surfactant and buffer solution were mixed, and the appropriate amount of drug was weighed and added to the aqueous solution while stirring with a low shear propeller mixer.
  • the temperature of the aqueous solution was maintained at 55-65°C.
  • all of the components of the oil phase were added into a separate container and heated to 75-85 0 C to melt and mix the components.
  • the aqueous phase was then added into the oil phase while maintaining the temperature above 70 0 C and mixing with a high shear homogenizer for a minimum of 15 minutes.
  • the emulsification process is best carried out in a conventional topical manufacturing equipment such as a Lee Kettle or Malt-Mat which allows for scraping of the materials from the sides of the vessel while the phases are being emulsified.
  • the product was cooled to 30 0 C. During this cooling time, the homogenizer speed was reduced and low agitation was used. After the product cooled, and the cream was produced, it can then be dispensed from the manufacturing vessel into holding containers. It can then be packed into tubes or sachets as necessary.
  • the product may be packed using blow-fill-seal (BFS) packaging technology, where the BFS tubes may be designed in such a way that it allows for ease of use across patient and hospital settings, allows for easy application and spreading onto the wound site, and maintains sterility of the product. This offers an advantage of less painful application than that of a cream.
  • BFS blow-fill-seal
  • the product may be formulated with lower viscosity and packaged into spray bottles, so that the product can be easily sprayed and applied to the wound site. This spraying provides an easier means to ensure complete coverage of the wound site without further contamination by the patient.
  • both the aqueous and oil phases may be filtered through a filter, for example, a 0.22 ⁇ m filter which removes all possible organisms, including spore-forming organisms.
  • the aqueous phase may be first filtered though a PALL cartridge filter (Pall Corporation, East Hill, NY, USA, 11548) which is contained in a heated filter housing directly into the manufacturing vessel. Thereafter, the oil phase is filtered through the same filter and filter housing, under positive pressure (20-30 psi, specifically 25 psi), thereby allowing for any remaining aqueous phase (containing drug) to also be carried into the manufacturing vessel. This minimizes active drug loss. As the oil phase is added into the already filtered aqueous phase, this manufacturing process uses phase inversion to manufacture the final water-in-oil cream.
  • PALL cartridge filter Pall Corporation, East Hill, NY, USA, 11548
  • the emulsion is manufactured by continuing to homogenize and agitate at high temperatures for a specified time period (10-20 mins, spec 15 min). Following the homogenization period, as previously described, the product is cooled while mixing, and then packaged after the final emulsion is formed.
  • the formulations of this invention may be evaluated to determine their ability to provide reasonable percutaneous flux through human skin.
  • the compounds and formulations for the topical administration according to the methods of this invention are to be used primarily for a localized action (e.g. prevention and treatment of scars), for which penetration across the skin is not necessary, in vitro human skin penetration assays are used as a surrogate to determine effectiveness of formulations. Positive results in these human skin penetration assays, which indicate permeation through the skin, suggests that drug will deposit within the skin layers, the target for pharmacological action.
  • solubility of the vitronectin receptor antagonist For purposes of preformulation of compounds of this invention, it is useful to first determine the solubility of the vitronectin receptor antagonist in question.
  • the physicochemical properties of a compound of formula Ia * render it to be a difficult to deliver molecule across the skin, since typically molecules should have a MW less than 300, and log D of ⁇ 2 at physiological pH, and should have a reasonable solubility in aqueous and lipoidal phases, to allow for optimal delivery in the skin layers.
  • the solubility of compound Ia in water is pH dependent as shown in Table 25. Consistent with the zwitterionic nature of compound Ia*, solubility was higher at the extreme ranges of the values tested and decreased as the pH became more neutral.
  • solubility was highest at pH 8 reaching close to 5 mg/mL
  • solubility of the compound in typical dermatological solvents was also tested as shown in Table 26.
  • Two important parameters for defining optimal delivery of molecules across the skin include: (a) amount of drug in solution in the formulation; and (b) use of penetration enhancers to improve delivery.
  • Table 27 lists some formulations that were prepared for flux studies.
  • Formulations prepared for the compound of formula Ia * used GRAS-listed excipients. Formulations were adapted to ensure that all drug is in solution in its respective phase. For this study, the drug concentration was capped at 1 % and 2%.
  • a series of solubility screening studies were completed prior to the formulation stage to determine the concentration of the compound of formula Ia * that could be dissolved in pure solvent, as well as in solvent: water systems.
  • PEG200, propylene glycol, benzyl alcohol and transcutol afforded the good solubility, and hence were used in the formulations.
  • Each of the formulations also included the use of known penetration enhancers.
  • the flux of the compound of formula Ia * ranged from below the level of quantitation to 2.77 ng/(cm 2* hr) from 0-4 hours exposure, 0.18 to 4.28 ng/(cm 2* hr) from 4-24 hours exposure, and 0.19 to 4.37 ng/(cm 2 *hr) from 0-24 hours exposure.
  • the highest drug flux over 24 hours was observed from the dual enhancer cream on the abraded skin (4.37 ng/(cm 2 *hr)).
  • the ointment formulation produced the next largest flux rate (0.58 ng/(cm 2* hr)).
  • the hydrophilic ointment produced comparable flux rates on both the intact skin and the abraded skin (0.19 ng/(cm 2 *hr) and 0.21 ng/(cm 2* hr), respectively).
  • the cumulative percent of the applied dose of the compound of formula Ia * penetrating the skin over the 24 hour duration of exposure ranged from 0.009% to 0.223%. The highest percent of applied dose penetrating the skin was observed with the dual enhancer cream on the abraded skin, 0.223%.
  • Table 28 lists some formulations exemplified in this invention together with flux data.
  • the protocol for conducting the in vitro skin flux is briefly as follows. Abraded dermatomed human abdominal skin was placed across two Franz diffusion cells. The skin was tape-stripped to reflect the wound indication. The formulation was placed in the donor cell, and samples were taken from the receptor cell at predetermined time intervals over a 24-hour period. Samples were analyzed using an LC-MS-MS method, and flux (permeation rate) calculated over 24 hours.
  • Target Flux Intact Skin: 200 ng/cm 2 /hr; Dermis alone (or abraded): 1000 ng/cm 2 /hr

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Birds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

The present invention describes methods and formulations using vitronectin receptor antagonists for the prevention of excessive scarring.

Description

METHODS AND FORMULATIONS
FIELD OF THE INVENTION
This invention relates to methods, topical formulations and methods of using topical formulations for the topical administration of vitronectin receptor antagonists for the prevention of excessive skin scarring.
BACKGROUND OF THE INVENTION lntegrins are a superfamily of heterodimeric transmembrane glycoproteins that are involved in adhesion as well as communication events. These heterodimeric transmembrane glycoproteins include αvβ3 (the vitronectin receptor). The vitronectin receptor αvβ3 is expressed on a number of cells, including endothelial, smooth muscle, osteoclast, and tumor cells, and, thus, it has a variety of functions. The OyB3 receptor expressed on the membrane of osteoclast cells mediates the adhesion of osteoclasts to the bone matrix, a key step in the bone resorption process. Ross, et al., J. Biol. Chem., 1987, 262, 7703. The αvβ3 receptor expressed on human aortic smooth muscle cells mediates their migration into neointima, a process which can lead to restenosis after percutaneous coronary angioplasty. Brown, et al., Cardiovascular Res., 1994, 28, 1815. Additionally, Okada, et al., Am. J. Pathol., 1996, 149(1), 37 suggest that ocvβ3 plays a role in vascular integrity and remodeling following focal ischemia within an infarcted area.
Additionally, it has been found that vitronectin receptor antagonists are useful in inhibiting adhesion formation, in particular, for the treatment of post-surgical adhesions US 2004/0142918.
Excessive scarring which can occur during the wound healing process can result in the formation of hypertrophic or keloid scars. Hypertrophic scars are those that stay within the boundaries of the initial wound while keloid scars spread from the initial wound and invade normal skin. Bayat A., McGrouther DA, Ferguson MWJ 2003 British Medical Journal, 326, 88-92; Brissett AE, Sherris DA 2001 Facial Plastic Surgery, 17 (4), 263-271. In addition to gross physical differences between hypertrophic scars and keloids, there are also microscopic differences in collagen organization and cellularity. Ehrlich HP, Desmouliere A, Diegelmann RF, Cohen IK, Compton CC, Garner WL, Kapanci Y1 Gabbiani G. 1994, American Journal of Pathology, 145(1 ), 105-113. Hypertrophic scars appear earlier than keloids: <4 weeks versus > 3 months to years after trauma. Hypertrophic scars may also slowly regress, though not disappear, while keloids continue to expand. Evidence in the literature indicates that hypertrophic scar formation may be related to the loss of control in the matrix production during the proliferation phase. Lygoe KA, Norman JT, Marshall JF, Lewis MP 2004 Wound Repair and Regeneration, 12, 461 -470. Fibroblast differentiation, survival and collagen production are the key steps involved in this process. Fibroblasts migrate in during the proliferation stage and begin to lay down collagen rich extracellular matrix. This migration is known to involve the expression of a number of integrins including αvβ3 and αvβ5. It has also been demonstrated that the adhesion of fibroblasts to the extracellular matrix via these integrins is at least partially responsible for triggering the synthesis of the collagen network. The antagonism of this binding would be expected to result in both a decreased fibrosis and a reduction in collagen synthesis and excessive scar formation. Av integrins are also involved in fibroblast differentiation to myofibroblasts. Blockade of αvβ3 and αvβ5 may also lead to decreased differentiation into myofibroblasts and a blunted response to growth factors such as transforming growth factor b (TGF-b). The importance of this blunted response is highlighted by the fact that TGF-b overproduction and a decrease in apoptosis of fibroblasts contribute to hypertrophic scar formation. Wang X, Smith P, Pu LLQ, Kim YJ, Ko F, Robson MC 1999 Journal of Surgical Research, 87, 194-200. Moulin V, Larochelle S, Langlois C, Thibault I, Lopez-Valle' CA, Roy M 2004, Journal of cellular Physiology, 198, 350-358. Recent research indicates that silicon sheets may reduce hypertrophic scars through an increase of basic fibroblast growth factor (bFGF) and a decrease in TGF-b rather than through direct pressure, increased oxygenation or increased hydration of the wound.
The management of hypertrophic scars and keloids is characterized by a wide variety of techniques. Many have been proven through extensive use over the last decades but few have been supported by prospective studies with adequate control groups and in some cases even safety data is missing. Nissen FB, Spauwen PH, Schalkwijk J, Kon M 1999, Plastic and Reconstructive Surgery, 104(5), 1435- 1458. Currently available treatments vary from surgery, pressure, corticosteroids, radiation, silicone, laser, cryotherapy, and experimental medications. With those therapies that have undergone clinical trials the results, particularly response rate and recurrence, are extremely variable. Multiple intralesional modalities have been tried including formalin, pepsin, HCI, oil of creosote, penacillamine, colchicines, 5- fluorouracil, bleomycin and interferon are a few. There are reports of successful animal studies with TGF modulators and with specific nontoxic inhibitors of collagen synthesis that can be applied locally. Early human trials using TGFs are in progress. Clearly there is still a deep and long felt need for new agents and formulations for the prevention of excess scar formation upon wound healing.
FIGURES
A brief description of the figures follows:
Fig 1. - in Vitro Percutaneous Absorption of Compound of Formula Ia* from Prototype Formulations Using Human Skin
SUMMARY OF THE INVENTION
The present invention provides methods of using vitronectin receptor antagonists for the prevention of excess scarring of skin, vitronectin receptor antagonist formulations suitable for topical application, and methods of using topical formulations of vitronectin receptor antagonists for the prevention of excess scarring of the skin in a mammal, in particular a human.
DETAILED DESCRIPTION OF THE INVENTION
In some embodiments, this invention describes a method of inhibiting excess scar formation on skin comprising the administration of a vitronectin receptor antagonist in a pharmaceutically acceptable formulation to a mammal in need thereof.
In some embodiments, the mammal to be treated is a human. In some embodiments, the methods of this invention comprise the topical administration of a vitronectin antagonist.
In some embodiments, the methods of this invention utilize a vitronectin receptor antagonist comprising a compound of formula I or II:
wherein: R is H, Ci.ealkyl, Ar, Het, or C1-6 alkylaryl;
R is R , A-Crj-4 alkyl, A-C2-4alkenyl, A-C2-4alkynyl, A-C3-4oxoalkenyl, A-C3-4oxoalkynyl, A-C-| ^aminoalkyl, A-C3.4aminoalkenyl, A-C3.4aminoalkynyl, unsubstituted or substituted by one or more of R1O or R7; A is H, C3-6cycloalkyl, Het or Ar;
R7 is -COR8, -COCR'2R9, -C(S)R8, -S(O)mOR', -S(O)mNR'R", -PO(OR'), -PO(OR')2, -NO2, or tetrazolyi; each R8 independently is -OR1, -NR1R", -NR'Sθ2R', -NR1OR1, or -OCR'2CO(O)R';
R9 is -OR1, -CN, -S(O)rR\ -S(O)mN(R')2, -C(O)R", C(O)N(R')2, or -CO2R';
R1O is H, halo, -OR11 , -CN, -NR1R11, -NO2, -CF3, CF3S(O)r, -CO2R1, -CON(R')2, A-Co-6alkyl-, A-Ci -βoxoalkyl-, A-C2-6alkenyI-, A-C2-6alkynyl-, A-Crj-6alkyloxy-, A-Crj-βalkylamino- or A-Crj-6alkyl-S(0)r-;
R1 1 is R', -C(O)R1, -C(O)N(R1J2, -C(O)OR', -S(O)mR', or -S(O)mN(R1)2;
-A-
W is -(CH Rg)3-U-(CH R9)b-;
U is absent or is CO, CRg2, C(=CRg2), S(O)k> O, NR9, CR9OR9, CRg(ORk)CR92, CR92CR9(ORk), C(O)CR92, CRg2C(O)1 CONR', NR'CO, OC(O), C(O)O, C(S)O, OC(S), C(S)NR9, NRgC(S), S(O)2NRg1 NR9S(O)2 N=N, NR9NRg,
NRgCRg21 CRg2NRg1 CRg2O1 OCRg2, c≡c Or CRg=CRg; G is NRe, S or O;
Rg is H1 C-j.galkyl, Het-Crj-galkyl, C3-7cycloalkyl-Cn-6a'kyl or Ar-Crj-6alkyl; Rk is R9, -C(O)R9, or -C(O)ORf;
R' is H, C-j _galkyl, Het-Cυ-6alkyl, C3-7cycIoalkyl-Co-6alkyl, Ar- Co-6a"<yl, or C-|.galkyl substituted by one to three groups chosen from halogen, CN, NRg2, ORg, SR9, CO2R9, and CON(Rg)2;
Rf is H, Chalky! or Ar-Co-6aIM;
RΘ is H, C-|_galkyl, Ar-Co-galkyl, Het-Co-6a'kyl. Cs-ycycloalkyl-Co-βalkyl, or (CH2)kCO2Rg;
R^ and Rc are independently selected from the group consisting of H, C-\. øalkyl, Ar-Co-6a'kyl, Het-Co-6alkyl, Cs-ecycloalkyl-Co-θalkyl, halogen, CF3, ORf, S(O)kRf, CORf, NO2, N(Rf)2j CO(NRf)2, and CH2N(Rf)2; or Rb and Rc are joined together to form a five or six membered aromatic or non-aromatic carbocyclic or heterocyclic ring, unsubstituted or substituted by up to three substituents chosen from the group consisting of halogen, CF3, C-^alkyl, 0Rf, S(O)kRf, CORf, CO2Rf, OH, NO2, N(Rf)2j CO(NRf)2, and CH2N(Rf)2 and methylenedioxy; Q"1 , Q2, Q3 and Q4 are independently N or C-Ry, provided that no more than one of Q1 , Q2, Q3 and Q4 is N;
R' is H, C-i-βalkyl, Ar-Crj-6alkyl or C3-6cycloalkyl-Co-6alkyl; R" is R1, -C(O)R1 or -C(O)OR1; R"' is H, C-μgalkyl, Ar-Co-βalkyl, Het-Cn-6alkyl, C3-6cycloalkyl-Co_6alkyl, halogen, CF3, 0Rf, S(O)|<Rf, CORf, NO2, N(Rf)2, CO(NRf)2, or CH2N(Rf)2;
Ry is H, halo, -0R9, -SR9, -CN, -NR9Rk, -NO2, -CF3, CF3S(O)n -CO2R9, -C0R9, -CONR92, or C-|-6alkyl unsubstituted or substituted by halo, -0R9, -SR9, -
CN, -NR9R", -NO2, -CF3, R1S(O)1--, -CO2Rg, -CORg, or -CONR92; a is O1 1 or 2; b is 0, 1 or 2; k is O, 1 or 2; m is 1 or 2; r is O, 1 or 2; s is 0, 1 or 2; u is O or 1; and v is O or 1 ; or a compound of formula Il
wherein
Ai is C or N;
E is a five- or six-membered heteroaromatic or six-membered aromatic ring optionally substituted by R3* or R4*;
X1-X2 is CHR1*-CH, CR1*=C, NR1*-CH, S(O)U*-CH, or 0-CH; X3 is CRδ'Rδ1*, NR5*, S(O)11* or O;
R'* is H, Ci-6 alkyl, Ar, Het, or C1-6alkylaryl; R"* is R'*, -C(O)R1* or -C(O)ORs*; R'"* is Cl -βalkyl, C3-7cycloalkyl-Co-4alkyl or Ar-Co-4alkyl; R1* is H, C-|-6alkyl, or Ar-Co-4alkyl;
R2* is -OR1*, -NR'*R"*, -NR'*Sθ2R"!*, -NROR'*, -OC(R1^C(O)OR1*, - OC(R'*)2θC(O)-R1*, -OC(R'*)2C(O)N(R1*)2, CF3 or COC(R^)2R2'*;
R2'* is -OR1*, -CN, -S(O)r*R'*, S(O)2N(R'*)2, -C(O)R1*, C(0)N(R'*)2 or - CO2R1*;
R5* and PS'* are independently H, Ci -galkyl, C3-7cycloalkyl-Co-4alkyl or Ar- Co-4alkyl;
R6* is W-(C(R1*)2)q*-Z*-(CR'*Ri0*)r*-U*-(C(R1*)2)s*-V*- or W'*-(C(R'*)2)q*- U*-(C(R'*)2)S *-; R3*, R4* and R7* are independently H, halo, -0R12*, -SR12*, -CN, -
NR'*R12*, -NO2, -CF3, CF3S(O)r*-, -CO2R1*, -CON(R'*)2, Ri4*-Cθ-6alkyl-, R14*- Ci-6oxoalkyl, Ri4*-C2-6alkenyh Ri4*-c2-6alkynyl, Ri4*-Co-6alkyloxy-, R14*-CO- 6alkylamino or Ri4*-Cn-6alkyl-S(O)r*-;
R8* is R1*, C(O)R1*, CN, NO2, Sθ2R'*or C(O)OR5*; R9* is R1*, -CF3, -SR1*, or -OR1*;
R1O* is H, C-|-4alkyl or -NR'*R"*;
R12* is R1*, -C(O)R1*, -C(O)N(R'*)2, -C(O)OR5*, -S(0)m*R'* or S(O)2N(R'*)2;
R14* is H, C3-6cycloalkyl, Het or Ar;
R15* is H, Ci-ioalkyl, Cs-ycycloalkyl-Co-salkyl or Ar-Crj-βalkyl; U* and V* are absent or are independently CO, C(R'*)2, C=C(Ri 5*)2, S(O)n*,
O, NR15*, CRiδ'ORiδ*, CR'*(OR"*)CR1*2, CR^CR1+(OR"*), C(0)C(R'*)2, C(R15*)2C(O), CONR15*, NR15*CO, OC(O), C(O)O, C(S)O, OC(S), C(S)NRi 5*, NR15*C(S), SO2NR15*, NR15*SO2, N=N, NR15*NR15*, NR15*C(R15*)2I NR15*C(R15*)2J C(R15*)2O, OC(R15*)2) C≡C, CR15*=CR15*, Het, or Ar, provided that U* and V* are not simultaneously absent;
W* is R'*R"*N-, R'*R"*NR'*N-, R'*R"*NR"*NCO-, R1*2NR'*NC(=NR'*)-, R1*0NR'*C(=NR1*)-,
.
W* is
Q* is NR'*, 0 or S;
Ra* is H, C-|-6alkyl, Ar-Co-6a"<yl, Het-Co-6alkyl, or Cs-Qcycloalkyl-Co-βalkyl, halogen OR"!*, SR1*, COR1*, OH, NO2, N(R1*)2) CO(NRi *)2, CH2N(Ri *)2;
Rb* and Rc* are independently selected from the group consisting of H, Ci- βa'kyl. Ar-Co-6alM. Het-Co-6alkyl, or Cs-βcycloalkyl-Co-βalkyl, halogen, OR1*, SR1*, COR1*, OH, NO2, N(R1*)2, CO(NR1*)2> CH2N(R1 *)2J or Rb* and Rc* are joined together to form a five or six membered aromatic non-aromatic ring, optionally substituted by halogen, Ci^alkyl, OR1*. SR1*, COR1 *, OH1 NO2, N(R1*)2, CO(NRi *)2J CH2N(Ri *)2, CN1 or R"*R'*NC(=NR'*)-; X* is N=CR1, C(O) or O;
Y* is absent, S or O;
Z* is (CH2)t*, Het, Ar or C3-7cycloalkyl;
M* is 1 or 2;
N* is 0, 1 , 2, or 3; q* is 0, 1 , 2, or 3; r* is 0, 1 or 2; s* is 0, 1 or 2; t* is 0, 1 or 2; u* is 0, 1 or 2; v* is 0 or 1 ; and w* is 0 or 1 ; or or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, the compound of formula I is Ia
Ia
wherein R is H, Ci-6alkyl, Ar, Het, Ci-6alkylaryl; or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, the compound of formula Ia is Ia*
Ia* or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula Il is Ha
Ha wherein R is H, C1-6alkyl, Ar, Het, C1-6alkylaryl; or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, the compound of formula Na is Ha*
(Ha*)
In some embodiments, this invention describes a method of inhibiting excess hypertrophic scar formation on skin comprising the topical administration of a pharmaceutically acceptable topical formulation comprising a carrier and a compound of formula I, II, Ia, Ha, Ia*, or Ha*, or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, this invention describes a formulation suitable for the topical administration of a compound of formula I or II,
(I) wherein:
R is H, Ci.6alkyl, Ar, Het, or Ct.6alkylaryl;
R is R , or A-Crj-4 alkyl-, A-C2-4alkenyl-, A-C2-4alkynyl-, A-C3-4θxoalkenyl-, A-C3-4oxoalkynyl-, A-Ci_4aminoalkyl-, A-C3_4aminoalkenyl-, A-C3_4aminoalkynyl-, optionally substituted by any accessible combination of one or more of R1 ° or R7; A is H, C3-6cycloalkyl, Het or Ar;
R7 is -COR8, -COCR'2R9, -C(S)R8, -S(O)mOR', -S(OJmNR1R", -PO(OR1), -P0(0R')2, -Nθ2, or tetrazolyl; each R8 independently is -OR1, -NR1R", -NR'SO2R', -NR1OR1, or -OCR'2CO(O)R";
R9 is -OR1, -CN, -S(O)rR', -S(O)nN(R^, -C(O)R1, C(O)N(R')2, Or -CO2R1;
R10 is H, halo, -OR1 1 , -CN, -NR1R1 1 , -NO2, -CF3, CF3S(0)r, -CO2R', -C0N(R')2, A-Co-6alkyl-, A-Ci _6oxoalkyl-, A-C2-6alkenyl-, A-C2-6alkynyl-, A-Co-6alkyloxy-, A-Co-6alkylamino- or A-Crj-6a|kyl-S(0)r-;
R1 1 is R1, -C(O)R1, -C(0)N(R')2, -C(O)OR", -S(O)nR', or -S(0)mN(R')2;
W is -(CHRg)a-U-(CHR9)b-; U is absent or is CO, CRQ 2, C(=CR92), S(0)k, 0, NR9, CR9OR9,
CRg(ORk)CRg2, CRg2CRg(ORk), C(O)CR92, CRg2C(O), CONR', NR'CO, OC(O), C(O)O, C(S)O, OC(S), C(S)NRg, NRQC(S), S(O)2NRS, NRSS(O)2 N=N1 NRSNRS, NRSCRg2, CRQ2NRg, CRS2O, OCRQ 2, C≡C Or CRg=CRS;
G is NRe, S or O;
RS is H, C-] _@alky[, Het-Co-galkyl, C3-7cycloalkyl-Co-6alkyl or Ar-Crj-6alkyl; Rk is RS, -C(O)RQ, or -C(O)ORf;
R' is is H, C-|_6alkyl, Het-Co-6a'kyl, C3-7cycloalkyl-Cø.-6alkyl, Ar" Co-galkyl, or C-j_5alkyl substituted by one to three groups chosen from halogen, CN, NRS2, ORS, SRS, CO2RS, and CON(RS)2;
Rf is H, C-] .øalkyl or Ar-Co-βalkyl; Re is H1 Ci-ρalkyl, Ar-Co-βalkyl, Het-Co-βalkyl, C3-7cycloalkyl-Co-6alkyI> or
(CH2)kCO2RS;
Rb and Rc are independently selected from the group consisting of H, C-] . galkyl, Ar-Co-6alkyl, Het-Crj-6alkyl, Cs-δcycloalkyl-Co-ealkyl, halogen, CF3, OR*,
S(O)kRf, CORf, NO2, N(Rf)2, CO(NRf)2, CH2N(Rf)2; or Rb and R° are joined together to form a five or six membered aromatic or non-aromatic carbocyclic or heterocyclic ring, optionally substituted by up to three substituents chosen from the group consisting of halogen, CF3, C-|_4alkyl, 0Rf, S(0)kRf, C0Rf, C02Rf, OH, NO2, N(Rf)2i CO(NRf)2, CH2N(Rf)2 and methylenedioxy;
Q1 , Q2, Q3 and Q4 are independently N or C-RY, provided that no more than one of Q1 , Q2, Q3 and Q4 is N;
R' is H, Ci-6alkyl, Ar-Crj-βalkyl or C3-6cycloalkyl-Cn,-6alkyl;
R" is R1, -C(O)R1 or -C(O)OR1;
R'" is H, Chalky], Ar-Co-βalkyl, Het-Co-βalkyl, C3-6cycloalkyl-Cn.-6alkyl, halogen, CF3, ORf, S(O)kRf, C0Rf, NO2, N(Rf)2j CO(NRf)2, or CH2N(Rf)2; Ry is H, halo, -ORS, -SRS, -CN, -NRSRk, _No2, -CF3, CF3S(O)n -CO2RS,
-CORS, -CONRS2, or C-|-6alkyl optionally substituted by halo, -ORS, -SRS, -CN,
-NRSR", -NO2, -CF3, R1S(O)n -CO2RS, -CORS or -CONRS2; a is 0, 1 or 2; b is 0, 1 or 2; k is 0, 1 or 2; m is 1 or 2; r is 0, 1 or 2; s is O, 1 or 2; u is 0 or 1 ; and v is 0 or 1 ; or a compound of formula Il
(H) wherein
A-| is C or N;
E is a five- or six-membered heteroaromatic or six-membered aromatic ring unsubstituted or substituted by R3* or R4*;
X1-X2 is CHR1 *-CH, CR1 *=C, NR1*-CH, S(O)U*-CH or O-CH; X3 is CR5*R5'*, NR5*, S(O)U* or O;
R'* is H, C1-6alkyl, Ar, Het, or C1-βalkylaryl;
R"* is R1*, -C(O)R1* or-C(O)OR5*;
R'"* is Ci-6alkyl, C3-7cycloalkyl-Co-4alkyl or Ar-Cn-4alkyl;
R1* is H, Ci-6alkyl, or Ar-Co-4alkyl; R2* is -OR1*, -NR^R"*, -NR'*Sθ2R'"*, -NROR1*, -OC(R1^C(O)OR'*, -
OC(R'*)2θC(O)-R'*, -OC(R'*)2C(O)N(R'*)2, CF3 or COC(R1^R2'*;
R2'* is -OR1*, -CN, -S(O)r*R'*, S(O)2N(R'*)2, -C(O)R1*, C(O)N(R'*)2 or - CO2R1*;
R5* and R5'* are independently H, Ci _6alkyl, C3-7cycloalkyl-Co-4alkyl or Ar- Cf>4alkyl;
R6* is W*-(C(R'*)2)q*-Z*-(CR"*RiO*)r*j -U*-(C(R'*)2)s*-V*-, or W'*-(C(R'*)2)q*- U*-(C(R1*)2)s*-;
R3*, R4* and R7* are independently H, halo, -OR12*, -SR12*, -CN, -
NR'*R12*, -NO2, -CF3, CF3S(O)r*-, -CO2R1*, -CON(R'*)2, Ri4*-Cθ-6a|ky|-, R14*. Ci -6oxoalkyl, Ri4*-c2-6alkenyl-, Ri4*-C2-6alkynyl, Ri4*-Co-6alkyloxy-, R14*-CO- βalkylamino or R14*-Cn-6alkyl-S(O)r*-;
R8* is R1*, C(O)R1*, CN, NO2, SO2R'*or C(O)OR5*;
R9* is R1*, -CF3, -SR'*, or -OR1*;
R1O* is H, Ci-4alkyl or -NR'*R"*; R12* is R1*, -C(O)R'*, -C(O)N(R'*)2, -C(O)OR5*, -S(0)m*R'* or S(O)2N(R'*)2;
R14* is H, C3-6cycloalkyl, Het or Ar;
R15* is H, Cl -1 oalkyl, C3-7cycloalkyl-Co-8all<yl or Ar-Co-8alkyl;
U* and V* are absent or are independently CO, C(R'*)2, C=C(Ri 5*)2, S(O)n*. O, NR15*, CR15-OR15*, CR"*(OR"*)CR'*2, CR'*2CR'*(OR"*), C(O)C(R'*)2, C(R15*)2C(O), CONR15*, NRi 5*C0, OC(O), C(O)O, C(S)O, OC(S), C(S)NRi 5*, NR15*C(S), SO2NRi 5*, NR15*SO2> N=N, NR15*NR15*, NR15*C(R15*)2J NR15*C(R15*)2) C(R15*)2O, OC(Ri 5*)2) C≡C, CR15*=CR15*, Het, or Ar, provided that U* and V* are not simultaneously absent;
W* is R'*R"*N-, R'*R"*NR'*N-, R'*R"*NR'*NC0-, R'* 2NR'*NC(=NR1*)-, R'*0NR'*C(=NR'*)-,
.
W* is
Q* is NR1*, O or S;
Ra* is H, Ci-βalkyl, Ar-Co-6a|W> Hθt-Co-6alkyl, or C3-6cycloalkyl-Cn-6alkyl> halogen OR1*, SR1*, COR1 *, OH, NO2, N(R1*)2, CO(NRi *)2, CH2N(R1*)2;
Rb* and Rc* are independently selected from H, C-|-6alkyl, Ar-Crj-6alkyl, Het- Co-βalkyl, or Cs-βcycloalkyl-Co-βalkyl, halogen, OR1*. SR1*. COR1*, OH, NO2, N(R1 *)2> CO(NRi *)2, CH2N(R1 *)2, or Rb* and Rc* are joined together to form a five or six membered aromatic non-aromatic ring, optionally substituted by halogen, Ci- 4alkyl, OR1*, SR1*, COR1*, OH, NO2, N(R1*)2, CO(NRi *)2> CH2N(R1*)2, CN, or R"*R'*NC(=NR'*)-;
X* is N=CR1, C(O) or O; Y* is absent, S or O; Z* is (CH2)f, Het, Ar or C3-7cycloalkyl; M* is 1 or 2;
N* is O, 1 , 2, or 3; q* is θ, 1 , 2, or 3; r* is 0, 1 or 2; s* is O, 1 or 2; t* is 0, 1 or 2; u* is 0, 1 or 2; v* is 0 or 1 ; and w* is 0 or 1 ; or a pharmaceutically acceptable salt or solvate thereof, wherein the formulation comprises from about 0.01 % to 50% w/w of the compound of formula I or Il and from about 0.5% to 99% of one or more penetration enhancers. In some embodiments of the formulations of this invention, the compound of formula I is Ia,
wherein R is H, d^alkyl, Ar, Het, C^salkylaryl; or a pharmaceutically acceptable salt or solvate thereof, and the compound of formula Il is Ha,
Na wherein R2* is H, C1-6alkyl, Ar, Het, C1-6alkylaryl; or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments of the formulations of this invention, the compound of formula Ia is 1a*,
(Ia*) or a pharmaceutically acceptable salt or solvate thereof, and the compound of formula Il is Na*,
(Ha*)
or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, this invention describes a formulation comprising a compound of formula I, II, Ia, Ha, Ia*, or Ha*, wherein the compound of formula I, II, Ia, Ha, Ia*, or Ha*, comprises from about O.01 % to 10% w/w of the formulation.
In some embodiments, this invention describes a formulation suitable for topical administration comprising a compound of formula I, II, Ia, Ha, Ia*, or Ha* and further comprising one or more penetration enhancers wherein the penetration enhancer or enhancers comprise from about 0.5% to 40% w/w of the formulation. In some embodiments, this invention describes a formulation suitable for topical administration comprising a compound of formula I, II, Ia, Ha, Ia*, or Ha* and further comprising one or more penetration enhancers wherein the penetration enhancer or enhancers comprise from about 0.5% to 25% w/w of the formulation.
In some embodiments, the formulations of this invention comprise a penetration enhancer selected from a group consisting of propylene glycol, benzyl alcohol, polyethylene glycols, dimethyl isosorbide, diethylene glycol monomethyl ether, macrogol 2 stearyl ethers, polyoxyl stearyl ethers, polyoxyl lauryl ethers, polyoxyl cetyl ethers, laurocapram, and caprylocaproyl macrogol-8 glycerides, or combinations thereof.
In some embodiments, formulations of this invention comprise a penetration enhancer or enhancers wherein said penetration enhancer or enhancers comprises propylene glycol. In some embodiments, formulations of this invention comprises a penetration enhancer or enhancers wherein said penetration enhancer or enhancers comprises at least one surfactant.
In some embodiments, the formulations of this invention have a pH of greater than about 7. In some embodiments, the formulations of this invention have a pH of greater than 8. In some embodiments, this invention describes a formulation having a pH of from about 8.5 to 9.5.
In some embodiments, the formulations of this invention comprise from about 1 % to 45% w/w of a buffer having a pH in the range of from 8 to 11. In some embodiments, the formulations of this invention comprise from about
25% to 75% w/w of one or more waxes, ointments, or bases, or combinations thereof.
In some embodiments, the formulations of this invention comprise from about 4% to 12% w/w of one or more emollients. In some embodiments, the formulations of this invention comprise from about
0.5% to 10% w/w of a surfactant.
In some embodiments, the formulations of this invention comprise from about 0.001 % to 2% of one or more antioxidants.
In some embodiments, the formulations of this invention comprise from about 0.05% to 5% of a compound of formula I, II, Ia, Ha, Ia*, or Ha*; from about 40% to 60% w/w of one or more waxes, ointments, or bases, or combinations thereof; from about 6% to 10% w/w of one or more emollients; from about 1.0% to 25% of one or more penetration enhancers; from about 0.01% to 1 % of one or more antioxidants; and from about 5% to 35% w/w of a pH 9-11 buffer. In some embodiments, the formulations of this invention comprise from about
0.1 % to 2% w/w of the compound of formula I, II, Ia, Ha, Ia*, or Ha*; from about 40% to 60% w/w of one or more waxes, ointments, or bases, or combinations thereof; from about 6% to 10% w/w of one or more emollients; from about 4.0% to 18% of one or more penetration enhancers; from about 0.01 % to 0.5% of one or more antioxidants; and from about 10% to 30% w/w of a pH 9.5-10.5 buffer.
In some embodiments, the formulations of this invention comprise from about 0.1 % to 2% w/w of the compound of formula I, II, Ia, lla, Ia*, or Ha*; from about 50% to 60% w/w of one or more waxes, ointments, or bases, or combinations thereof; from about 7% to 9% w/w of one or more emollients; from about 10.0% to 18% of one or more penetration enhancers; from about 0.01 % to 0.2% of one or more antioxidants; and from about 20% to 28% w/w of a pH 9.5-10.5 buffer.
In some embodiments, the formulations of this invention comprise from about 0.1 -1.0% of the compound of formula I, II, Ia, lla, Ia*, or lla*,; from about 45% to 55% petrolatum; from about 6% to 10% mineral oil; from about 3% to 8% polyoxyl stearyl ether; from about 0.01 % to 0.1 % butylated hydroxyanisole; and from about 20% to 28% w/w borate buffer with a pH about 10. In some embodiments, this invention describes a method of preventing excessive scarring comprising the topical administration of a formulation of this invention, wherein said administration is to a mammal's skin, wherein said skin has been cut, split, torn, or otherwise injured in such a way that excessive scarring upon healing might result.
In some embodiments, this invention describes a method of preventing excessive scarring comprising the topical administration of a formulation of this invention, wherein said administration is to a human's skin, wherein said skin has been cut, split, torn, or otherwise injured in such a way that excessive scarring upon healing might result.
In some embodiments, the methods of his invention comprise the repeated administration of a topical formula of this invention.
In some embodiments, the excessive scarring to be prevented is hypertrophic. For purposes of this invention, definitions as they apply to the structural formulae descriptors are as follows: C-\ .4 alkyl as applied herein means an optionally substituted alkyl group of 1 to 4 carbon atoms, and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl. C-μβalkyl additionally includes pentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof. Cn-4alkyl and Co-6alM additionally indicates that no alkyl group need be present (e.g., that a covalent bond is present).
C2.6alkenyl as applied herein means an alkyl group of 2 to 6 carbons wherein a carbon-carbon single bond is replaced by a carbon-carbon double bond. C2-5 alkenyl includes ethylene, 1-propene, 2-propene, 1-butene, 2-butene, isobutene and the several isomeric pentenes and hexenes. Both cis and trans isomers are included.
C2.6alkynyl means an alkyl; group of 2 to 6 carbons wherein one carbon- carbon single bond is replaced by a carbon-carbon triple bond. C2.6alkynyl includes acetylene, 1 -propyne, 2-propyne, 1 -butyne, 2-butyne, 3-butyne and the isomers of pentyne and hexyne.
Ci.4oxoalkyl refers to an alkyl group of up to four carbons wherein a CH2 group is replaced by a C(O), or carbonyl group. Substituted formyl, acetyl, 1- propanal, 2-propanone, 3-propanal, 2-butanone, 3-butanone, 1- and 4-butanal groups are representative. d.6oxoalkyl includes additionally the higher analogues and isomers of five and six carbons substituted by a carbonyl group. C3.β oxoalkenyl and C3-6 oxoalkynyl refers to a C3.6 alkenyl or C3.6alkynyl wherein a CH2 group is replaced by a C(O) group. C3.4 oxoalkenyl includes 1 -oxo-2-propenyl, 3-oxo-1- propenyl, 2-oxo-3-butenyl and the like.
Any C-| _4alkyl or C-^ .Q alkyl, C2-6 alkenyl, C2-6 alkynyl, C1.4 oxoalkyl, C-\ .Q oxoalkyl, C3-4 oxoalkenyl, C3-6 oxoalkenyl and C3.6oxoalkynyl may be optionally substituted with the group Rx, which may be on any carbon atom that results in a stable structure and is available by conventional synthetic techniques. Suitable groups for Rx are C-j^alkyl, OR1, SR", C-^alkylsulfonyl, C-j ^alkylsulfoxyl, -CN,
N(R')2, CH2N(R')2, -NO2, -CF3, -CO2R" -CON(R')2, -COR', -NR1C(O)R1, F, Cl, Br, I, or CF3S(O)r,wherein r is 0, 1 or 2. R14*-CI -6 alkyl refers to a Ci -6 alkyl group wherein in any position a carbon- hydrogen bond is replaced by a carbon-Ri4* bond. Ri4*-C2-6 alkenyl and R14*-C2- 6 alkynyl have a similar meaning with respect to C2-6 alkenyl and C2-6 alkynyl. Halogen or halo means F, Cl, Br, and I.
Ar, or aryl, as applied herein, means phenyl or naphthyl, or phenyl or naphthyl substituted by one to three substituents, such as those defined above for alkyl, especially C^alkyl, C-^alkoxy, C^alkylthio, CF3, NH2, OH, F, Cl, Br or I.
Het, or heterocycle, indicates an optionally substituted five or six membered monocyclic ring, or a nine or ten-membered bicyclic ring containing one to three heteroatoms chosen from the group of nitrogen, oxygen and sulfur, which are stable and available by conventional chemical synthesis. Illustrative heterocycles are benzofuryl, benzimidazole, benzopyran, benzothiophene, furan, imidazole, indoline, morpholine, piperidine, piperazine, pyrrole, pyrrolidine, tetrahydropyridine, pyridine, thiazole, thiophene, quinoline, isoquinoline, and tetra- and perhydro- quinoline and isoquinoline. Any accessible combination of up to three substituents on the Het ring, such as those defined above for alkyl that are available by chemical synthesis and are stable are within the scope of this invention.
C3-7cycloalkyl refers to an optionally substituted carbocyclic system of three to seven carbon atoms, which may contain up to two unsaturated carbon-carbon bonds. Typical of C3-7cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl and cycloheptyl. Any combination of up to three substituents, such as those defined above for alkyl, on the cycloalkyl ring that is available by conventional chemical synthesis and is stable, is within the scope of this invention. As used herein ^ indicates a nitrogen heterocycle, which may be a saturated or unsaturated stable five-, six- or seven-membered monocyclic ring, or a seven- to ten-membered bicyclic ring containing up to three nitrogen atoms or containing one nitrogen atom and a heteroatom chosen from oxygen and sulfur, and which may be substituted on any atom that results in a stable structure. The nitrogen atom in such ring may be substituted so as to result in a quaternary nitrogen. The nitrogen heterocycle may be substituted in any stable position by H, Ci-4alkoxy, F,
Cl, Br, I, NO2, N(R'*)2, OH, CO2R'*, CONHR1*, CF3, Ri4*-Cυ-4alkyl, R14*-CI - 4alkyl-S(O)u* (e.g., where u* is 0, 1 or 2) or Ci-4alkyl substituted by any of the
aforementioned substituents. Representative of ^ are pyrroline, pyrrolidine, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyraxolidine, piperidine, piperazine, morpholine, pyridine, pyridinium, tetrahydropyridine,tetrahydro- and hexahydro-azepine, quinuclidine, quinuclidinium, quinoline, isoquinoline, and tetra- and perhydro- quinoline and isoquinoline. In particular, ^ may be pyridyl, pyrolidinyl, piperidinyl, piperazinyl, azetidinyl, quinuclidinyl or tetrahydropyridinyl. ^ is preferably 4-pyridyl, 4-(2-amino-pyridyl), 4-tetrahydropyridyl, 4-piperidinyl or 4- piperazinyl.
When Rb and Rc are joined together to form a five- or six-membered aromatic or non-aromatic carbocyclic or heterocyclic ring fused to the ring to which R^ and Rc are attached, the ring formed will generally be a five- or six-membered heterocycle selected from those listed above for Het, or will be a phenyl, cyclohexyl or cyclopentyl ring. Preferably Rj3 and Rc will be -D1=D2-D3=D4 wherein D1 - D4 are independently CH, N or C-Rx with the proviso that no more than two of D1 - D4 are N. Most preferably, when R^ and Rc are joined together they form the group -CH=CH-CH=CH-.
Certain radical groups are abbreviated herein. t-Bu refers to the tertiary butyl radical, Boc refers to the t-butyloxycarbonyl radical, Fmoc refers to the fluorenylmethoxycarbonyl radical, Ph refers to the phenyl radical, Cbz refers to the benzyloxycarbonyl radical, Bn refers to the benzyl radical, Me refers to methyl, Et refers to ethyl, Ac refers to acetyl, AIk refers to C^ _4alkyl, Nph refers to 1 - or
2-naphthyl and cHex refers to cyclohexyl. Tet refers to 5-tetrazolyl.
The preparation of the compounds of this invention are described in WO 98/14192 and US 6,495,560. This invention describes methods of using vitronectin receptor antagonists for the prevention of scarring and can be administered via any method deemed appropriate to accomplish that purpose. It is preferred that the methods of this invention utilize a topical administration of a vitronectin receptor antagonist. The methods of this invention may be used to treat or prevent scarring or excess scar formation. By prevention of excess scarring, it is meant that the methods of this invention are preferably utilized before a scar has healed entirely. Some non-limiting examples of vitronectin receptor antagonists useful for the purposes of this invention are described in include those described in the following: PCT Application No. PCT/US95/08306, published as WO 96/00730; PCT Application No. PCT/US95/08146, published as WO 96/00574; PCT Application No. PCT/US96/11108, published as WO97/01540; PCT Application No. PCT/US96/20748, published as WO 97/24119; PCT Application No. PCT/US96/20744, published as WO WO97/24122; PCT Application No. PCT/US96/20327, published as WO 97/24124; PCT Application
No.PCT/US98/00490, published as WO 98/30542; PCT Application No. PCT/US98/19466, published as WO 99/15508; PCT Application No. PCT/US99/28622, published as WO 00/33838, which are herein incorporated by reference. In some aspects, this invention provides a formulation comprising a compound of formula I, II, Ia, Ha, Ia*, or Ha* which is suitable for topical administration. In some embodiments, the compound of formula I, II, Ia, Ha, Ia*, or Ha* is present in from about 0.01 % to 99% w/w of the formulation, or from about 0.01% to 50%, or from about 0.01 to 10%, or from about 0.05% to 5%, or from about 0.1 % to 2%, or from about 0.1 % to 1 %, or about 2%, or about 1 %, or about 0.5%, or about 0.1 %.
In certain embodiments, this invention describes a compound of formula I, II, Ia, Ha, Ia*, or Ha* which is suitable for topical administration wherein said formulation includes at least one penetration enhancer. For purposes of this invention, a penetration enhancer is any substance which facilitates the absorption of a substance through the skin and for purposes of this invention, water is excluded from the definition of a penetration enhancer. Also to be excluded from the definition of a penetration enhancer is any substance whose primary purpose is as a wax, ointment, base or emollient. Penetration enhancers may sometimes serve as drug substance solubilizers. Among the classes of compounds useful as penetration enhancers are low molecular weight alcohols such as methanol, ethanol, 2-propanol, propylene glycol, and the like. Higher molecular weight alcohols may also be sometimes used, such as polyethylene glycols (PEG), and the like. Alkyl methyl sulfoxides such as dimethyl sulfoxide (DMSO), decylmethyl sulfoxide or tetradecylmethyl sulfoxide and the like, may also be useful. Pyrrolidinones such as 2-pyrrolidinone, N-methyl-2- pyrrolidinone or N-(2-Hydroxyethyl)pyrrolidone, and the like, might also be useful. Laurocapram might also be useful as well as additional miscellaneous solvents such as acetone, dimethyl acetamide, dimethyl formamide, glycol ethers (such as diethylene glycol monomethyl ether (Transcutol®), caprylocaproyl macrogol-8 glycerides (Labrasol®), or tetrahydrofurfuryl alcohol, and the like, might also be useful for the formulations and methods of this invention. Surfactants might also serve as penetration enhancers. Surfactants include amphiphilic molecules such as anionic surfactants, cationic surfactants, amphoteric surfactants, nonionic surfactants (such as polyoxyethylene alkyl ethers including macrogol 2 stearyl ethers, polyoxyl stearyl ethers, polyoxyl lauryl ethers, polyoxyl cetyl ethers) and fatty acids or alcohols (such as benzyl alcohol). The penetration enhancer or enhancers may be present in any amount deemed to be effective for the particular formulation and indication being studied. In some embodiments, the penetration enhancer or enhancers is present in from .5% to 99%, in some embodiments .5% to 40%, in some embodiments .5% to 25%, in some embodiments 1% to 25%, in some embodiments 4% to 18%, in some embodiments 10% to 18%, in some embodiments 10%, or 11%, or 12%, or 13%, or 14%, or 15%, or 16%.
In some embodiments, the formulations of this invention include one or more waxes, ointments, or bases, or a combination thereof. In the broader sense, ointments, bases or waxes of this invention typically include semisolid substances which serve as vehicles for the delivery of the drug substance while not undergoing significant absorption itself. Ideally, these substances are compatible with the skin, possess good stability, are smooth and readily applied (pliable), are not irritating or sensitizing, and are capable of delivering the drug substance. Substances serving as waxes, oils, or ointments in this invention are preferably not highly absorbed by the skin. Useful bases include petrolatums such as white petroleum jelly, yellow petroleum jelly, polyethylene glycol, and mineral jelly, and the like. In some embodiments, the wax, ointment, or base, or combination thereof, is present in from 0.5% to 99%, in some embodiments from 25% to 75%, in some embodiments from 40% to 60%, in some embodiments from 50% to 60%, in some embodiments 45% to 55%, in some embodiments about 50%, or about 51 %, or about 52%, or about 53%, or about 54%, or about 55%, or about 56%, or about 57%, or about 58%.
In certain embodiments, the formulations of this invention, and methods of treatment using the formulations of this invention include a pH-buffered solution. In some embodiments, the pH-buffered solution is present in from about 0.5% to 65% w/w of the formulation, in some embodiments from about 1 % to 45% w/w; or from about 5% to 35% w/w; or from about 10% to 30% w/w; or from about 20% to 28% w/w; or about 24%. The pH buffer of this invention facilitates the transport of the compounds of this invention, especially where said compounds are capable of forming zwitterionic salts. In the case where a compound of this invention can form a zwiterrionic salt, the buffer can serve to facilitate the deprotonation of said salt and thus reduce the zwitterionic character of the drug substance. The pH of the buffer selected as well as the chemical make up of the buffer are to be determined primarily by the contents of the formulation, including the drug used in the formulation. In certain embodiments, the buffers used in the formulations of this invention have a pH of about 8 to 11 ; or about 9 to 11 ; or about 9.5 to 10.5; or about 9.6 to 10.4, or about 10. In some embodiments, the pH buffers of this invention consist of a weak acid and its conjugate base. Some non-limiting examples of buffers of this invention include (H3BO3Z[B(OH)4]"); (HCO3VCO3 2-); (HSO4VSO4 2-); (H2PO4V HPO4 2"); citrate/citric acid; and tartrate/tartaric acid.
The pH of the topical formulations of this invention may be controlled by the inclusion of an acid or base buffer, or a pharmaceutically acceptable acid or base in a non-buffered embodiment. In this non-buffered context, the base or acid used maybe organic or inorganic. In certain embodiments, the formulations of this invention have pHs of >7, or >8, or about from 8.5 to about 9.5, or from about 8 to about 9, or from about 7.5 to 8.5, or from about 7 to about 9, or from about 8.5 to 8.7. In certain embodiments, it is advantageous to utilize formulations that have their pHs controlled primarily with a pharmaceutically acceptable acid. Such acids can be used to bring the pH down into a desired range of less than 7, or less than 6, or from about 5 to 7, or from about 4 to 6, or from about 3 to 6, or about 4.
In some embodiments, the formulations of this invention include one or more emollients. Emollients are typically bland, fatty or oleaginous substances which helps to both soften the skin as well as protect the skin from various air born contaminants while the skin heals. Some non-limiting examples of emollients useful for the purposes of this invention include cetostearyl alcohol, sesame oil, lanolin, mineral oil, coconut oil, sulfated castor oil, petrolatum, corn oil, isopropyl palmitate, cetyl esters wax, lecithin, cholesterol, glycerol, glyceryl monostearate, castor oil, isopropyl myristate, mineral oil, petrolatum (white or yellow), petrolatum alcohols, cold cream, cotton seed oil, hydrophilic ointment, rose water ointment, and theobroma oil. The emollient or emollients, if used, may be present in any amount deemed beneficial to the particular formulation contemplated. For example, an emollient or emollients maybe present in from about 0.1 % to 65% w/w of the formulation, or from about 0.5% to 45%, or from about 2% to 25%, or from about 4% to 15%, or from about 4% to 12%, or from about 6% to 10%, or from about 7% to 9%, or from about 6%, or about 7%, or about 8%, or about 9% or about 10%. In some embodiments, the formulations of this invention include one or more antioxidants. For purposes of this invention, an antioxidant is any substance that can prevent, hinder, slow or otherwise inhibit the oxidative deterioration of any component of the formulation. Some non-limiting examples of antioxidants contemplated for use in this invention include ascorbic acid, ascorbic acid esters, butylated hydroxyanisole, butylated hydroxytoluene, sodium or potassium metabisulfite, sodium or potassium bisulfite, fumaric acid, malic acid, alpha tocopherol, or propyl gallate. In some embodiments, the formulations of this invention contain from about 0.001% to 5% antioxidant, or from about 0.001% to 4%, or from about 0.001 % to 3%, or from about 0.001 % to 2%, or from about 0.01 % to 1 %, or from about 0.01 % to 0.5%, or from about 0.01 % to 0.4%, or from about 0.01 % to 0.3%, or from 0.01 % to 0.2%; or from about 0.1 % to 1%, or from about 0.1 % to 0.5%, or from about 0.1% to 0.4%, or from about 0.1% to 0.3%, or from about 0.1% to 0.2%, or about 0.1%, or about 0.2%, or about 0.3%, or about 0.4%, or about 0.5%. In some embodiments, the formulations of this invention may include an antimicrobial agent. Some non-limiting examples of antimicrobial agents contemplated for the purposes of this invention are benzoic acids or benzoate salts, editic acid, phenol, sorbic acid, benzyl alcohol, isopropyl alcohol, benzethonium chloride, propylparaben, imidurea, propionate salts, bronopol, butylparaben, cetrimide, chlorhexidine, phenylmercuric nitrate, potassium sorbate, propylene glycol, chlorbutanol, chlorocresol, cresol, ethylparaben, glycerol, methylparaben, phenoxyethanol, phenethyl alcohol, phenylmercuric acetate, phenylmercuric borate, and thimersol.
It is to be understood that formulations of this invention are comprised of various possible combinations of those ingredients or excipients listed above. Accordingly, formulations may comprise combinations of those ingredients in the described ranges or the formulation may comprise subcombinations of ingredients or excipients listed above wherein not every category of excipient or ingredient is represented in every formulation.
Furthermore, it is to be understood that any of the methods of this invention maybe combined with any of the formulation embodiments of this invention and that this invention is not limited to the specifically enumerated embodiments. Typical Formulations Table 1
Table 7
Table 8
Ingredients Ranges
Compound of Formula I or Il 0.05% to 5% w/w
Wax(es)/Ointment(s)/Base(s) 40% to 60%
Emollient(s) 6% to 10%
Penetration Enhancer(s) 1 % to 25%
Antioxidant(s) 0.01 % to 1 %
Buffer(s) 5 - 35% (pH 9-11)
Additional Ingredients qs to 100%
Table 9
Ingredients Ranges
Compound of Formula I or Il 0.1% to 2% w/w
Wax(es)/Ointment(s)/Base(s) 40% to 60%
Emollient(s) 6% to 10%
Penetration Enhancer(s) 4% to 18%
Antioxidant(s) 0.01% to 0.5%
Buffer(s) 10 - 30% (pH 9.5-10.5)
Additional Ingredients qs to 100%
Table 10
Ingredients Ranges
Compound of Formula I or II 0.1 % to 1 % w/w
Wax(es)/Ointment(s)/Base(s) 50% to 60%
Emollient(s) 7% to 9%
Penetration Enhancer(s) 10% to 18%
Antioxidant(s) 0.01% to 0.2%
Buffer(s) 20 - 28% (pH 9.6-10.4)
Additional Ingredients qs to 100%
Table 11
Ingredients Ranges
Compound Ia* or Ha* 0.01% to 10% w/w
Wax(es)/Ointment(s)/Base(s) 25% to 75%
Emollient(s) 4% to 12%
Penetration Enhancer(s) 0.5% to 40%
Antioxidant(s) 0.001% to 2%
Buffer(s) 1 - 45% (pH 8-11)
Additional Ingredients qs to 100% Table 12
Ingredients Ranges
Compound Ia* or Ha* 0.05% to 5% w/w
Wax(es)/Ointment(s)/Base(s) 40% to 60%
Emollient(s) 6% to 10%
Penetration Enhancer(s) 1% to 25%
Antioxidant(s) 0.01 % to 1%
Buffer(s) 5 - 35% (pH 9-11)
Additional Ingredients qs to 100%
Table 13
Ingredients Ranges
Compound Ia* or Na* 0.1% to 2% w/w
Wax(es)/Ointment(s)/Base(s) 40% to 60%
Emollient(s) 6% to 10%
Penetration Enhancer(s) 4% to 18%
Antioxidant(s) 0.01% to 0.5%
Buffer(s) 10 - 30% (pH 9.5-10.5)
Additional Ingredients qs to 100%
Table 14
Ingredients Ranges
Compound Ia* or Ha* 0.1 % to 1 % w/w
Wax(es)/Ointment(s)/Base(s) 50% to 60%
Emollient(s) 7% to 9%
Penetration Enhancer(s) 10% to 18%
Antioxidant(s) 0.01% to 0.2%
Buffer(s) 20 - 28% (pH 9.6-10.4)
Additional Ingredients qs to 100%
EXAMPLES
Table 15 Example Formulation 1 (cream)
Table 16 Example Formulation 2 (cream)
Table 17 Example Formulation 3 (cream)
Table 18 Example Formulation 4 (ointment)
Table 19 Example Formulation 5 (ointment)
Table 20 Example Formulation 6 (cream)
Table 21 Example Formulation 7 (gel)
Table 22 Example Formulation 8 (gel)
Ingredients Ranges
Compound Ia* 1.0%
Carbopol 934P 1.0%
Transcutol 50%
Purified water 48%
Table 23 Example Formulation 9 (solution)
Ingredients Ranges
Compound Ia* 2.0%
Transcutol 98%
Table 24 Example Formulation 10 (solution)
The methods of this invention are directed to the administration of vitronectin receptor antagonists which are useful for the prevention of excessive scarring of skin. In some embodiments, the formulations of this invention are useful for the treatment of normal, hypertrophic or keloid scarring. In some embodiments, the formulations of this invention maybe used to prevent hypertrophic or normal scarring. In some embodiments, the formulations of this invention maybe used as a method of treating hypertrophic scarring. The methods of this invention relate to the prevention of scarring of the skin which occurs after an injury or insult to the skin, most often in the form of a cut or splitting in the skin which upon healing, might form a normal scar, a hypertrophic scar or a keloid scar. The treatment methods of this invention comprise the administration of a vitronectin receptor antagonist, wherein said administration may be oral, parenteral, inhaled, topically, or through a mucous membrane via insert or suppository. The compositions of vitronectin receptor antagonists useful for the purposes of this invention may be formulated as solutions or lyophilized powders for parenteral administration. Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use. Liquid formulations useful for the methods of this invention may be buffered or non-buffered. Some examples of suitable diluents are normal isotonic saline solutions, standard 5% dextrose in water or buffered sodium or ammonium acetate solution. While such formulations are especially suitable for parenteral administration, they may also be used in oral administrations, or contained in a metered dose inhaler or a nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidinone, gelatin, mannitol, sodium chloride or sodium citrate.
Alternatively, these compounds may be encapsulated, tableted or prepared in an emulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, pectin, acacia, agar or gelatin. Liquid carriers include syrup, peanut oil, olive oil, saline and water. The carrier may include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier may vary according to the need, but typically will include between 10 mg and 750 mg per dosage unit. These pharmaceutical preparations can be made according to conventional techniques such as milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms. If a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Such a liquid formulation may be administered directly p.o. or filled in a soft gelatin capsule.
Rectal or vaginal administration may also be used to perform the methods of this invention and accordingly, vitronectin receptor antagonists may be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded or formed into a suppository.
When a vitronectin receptor antagonist is administered orally, the typical dosage will be between 0.1 mg/kg and 50 mg/kg, depending upon the particular antagonist used as well as the particulars of the patient's condition and presentation. Preferably, the oral dosage will be between 0.5 mg/kg and 25 mg/kg. For acute administration, an intravenous infusion of the vitronectin receptor antagonist in an aqueous solution may be preferable. For these purposes, the vitronectin receptor antagonist may be conveniently coadministered, if desired, with other substances via the IV. Typically, a dose via IV will be between 0.1 mg/kg and 20 mg/kg and may be administered as needed. Alternatively, the vitronectin receptor antagonist may be administered via a depot formulation wherein the substance is injected or placed into a subdermal depot and allowed to release over a period of time. Vitronectin receptor antagonists may also be injected intradermally which is accomplished by injection of a vitronectin antagonist near the wound site. The injections may be administered once or as part of a series of injections depending on what the situation dictates. In some embodiments, this invention describes the topical application of a vitronectin receptor antagonist to injured skin in order to prevent excess scarring. In some embodiments, the formulation of this invention may be topically applied once and in some embodiments, the formulation will need to be applied repeatedly. By repeated applications, it is meant that the formulation will be applied and then after a period of time, another application will be made, and so on until the desired level of benefit is achieved. The treatment regimen maybe comprised of formulations of this invention administered prior to, or coadministered or administered subsequently to therapy with other known or possible scar formation palliatives including surgery, pressure, corticosteroids, radiation, silicone, laser, cryotherapy, formalin, pepsin, HCI, oil of creosote, penacillamine, colchicines, 5-fluorouracil, bleomycin and interferon.
The formulations of this invention may be administered in any form suitable for a topical administration. A formulation of this invention may be prepared as, and administered, for example, a cream, ointment, solution, gel, salve, emulsion, lotion, suspension or a semi-solid. The methods and formulations of this invention may also be administered with a wound healing device. For example, a bandage, wrap, cast and the like, may be impregnated with a vitronectin receptor antagonist and be placed over the wound site, and the device changed as needed. Cream formulations are generally prepared using an emulsification process whereby the aqueous and oil phases are first prepared in separate vessels. Temperatures of both phases are maintained at high temperatures, and while hot, one phase is added to another while mixing using a high shear mixer. The final emulsion is allowed to cool, while the agitation continues at lower speeds. The cream can then be dispensed from the manufacturing vessel and filled into the primary pack, such as, for example, a tube or sachet.
The cream formulations of Example formulation #1 (Table 15), #2 (Table 16), or #3 (Table 17) in this invention were manufactured by first preparing the aqueous phase. The surfactant and buffer solution were mixed, and the appropriate amount of drug was weighed and added to the aqueous solution while stirring with a low shear propeller mixer. The temperature of the aqueous solution was maintained at 55-65°C. Concurrently, all of the components of the oil phase were added into a separate container and heated to 75-850C to melt and mix the components.
The aqueous phase was then added into the oil phase while maintaining the temperature above 700C and mixing with a high shear homogenizer for a minimum of 15 minutes. The emulsification process is best carried out in a conventional topical manufacturing equipment such as a Lee Kettle or Malt-Mat which allows for scraping of the materials from the sides of the vessel while the phases are being emulsified. Following the emulsification time of 15 minutes, the product was cooled to 300C. During this cooling time, the homogenizer speed was reduced and low agitation was used. After the product cooled, and the cream was produced, it can then be dispensed from the manufacturing vessel into holding containers. It can then be packed into tubes or sachets as necessary.
Additionally, as the product will be used for open wounds, it may be packed using blow-fill-seal (BFS) packaging technology, where the BFS tubes may be designed in such a way that it allows for ease of use across patient and hospital settings, allows for easy application and spreading onto the wound site, and maintains sterility of the product. This offers an advantage of less painful application than that of a cream. As a further packaging option for this product and its variations, the product may be formulated with lower viscosity and packaged into spray bottles, so that the product can be easily sprayed and applied to the wound site. This spraying provides an easier means to ensure complete coverage of the wound site without further contamination by the patient.
To manufacture a product with low bio-burden (ie aseptic conditions), both the aqueous and oil phases may be filtered through a filter, for example, a 0.22 μm filter which removes all possible organisms, including spore-forming organisms.
For example, the aqueous phase may be first filtered though a PALL cartridge filter (Pall Corporation, East Hill, NY, USA, 11548) which is contained in a heated filter housing directly into the manufacturing vessel. Thereafter, the oil phase is filtered through the same filter and filter housing, under positive pressure (20-30 psi, specifically 25 psi), thereby allowing for any remaining aqueous phase (containing drug) to also be carried into the manufacturing vessel. This minimizes active drug loss. As the oil phase is added into the already filtered aqueous phase, this manufacturing process uses phase inversion to manufacture the final water-in-oil cream. Once both phases have been filtered into the manufacturing vessel, the emulsion is manufactured by continuing to homogenize and agitate at high temperatures for a specified time period (10-20 mins, spec 15 min). Following the homogenization period, as previously described, the product is cooled while mixing, and then packaged after the final emulsion is formed. The formulations of this invention may be evaluated to determine their ability to provide reasonable percutaneous flux through human skin. Although the compounds and formulations for the topical administration according to the methods of this invention are to be used primarily for a localized action (e.g. prevention and treatment of scars), for which penetration across the skin is not necessary, in vitro human skin penetration assays are used as a surrogate to determine effectiveness of formulations. Positive results in these human skin penetration assays, which indicate permeation through the skin, suggests that drug will deposit within the skin layers, the target for pharmacological action.
For purposes of preformulation of compounds of this invention, it is useful to first determine the solubility of the vitronectin receptor antagonist in question. The physicochemical properties of a compound of formula Ia* render it to be a difficult to deliver molecule across the skin, since typically molecules should have a MW less than 300, and log D of ~ 2 at physiological pH, and should have a reasonable solubility in aqueous and lipoidal phases, to allow for optimal delivery in the skin layers. For example, the solubility of compound Ia in water is pH dependent as shown in Table 25. Consistent with the zwitterionic nature of compound Ia*, solubility was higher at the extreme ranges of the values tested and decreased as the pH became more neutral. Within the tested range, solubility was highest at pH 8 reaching close to 5 mg/mL The solubility of the compound in typical dermatological solvents was also tested as shown in Table 26. These results indicate that despite its zwitterionic nature, the compound of formula Ia* solubility may be improved in a dermatological formulation through appropriate use of co-solvents.
Table 25 pH-Solubility Profile of Compound of Formula Ia*
As a result of the low aqueous solubility of the compound of formula Ia*, it was critical to improve its solubility profile in the formulation. A number of solvents were evaluated to enhance the amount of Ia* that could be delivered in solution. Some penetration enhancers tested include propylene glycol, polyethylene glycol, ethylene diglycol, polysorbate 80, amongst others.
Table 26 Solubilit of Com ound of Formula Ia* in Select Solvents for To ical Formulation1'
Single determination using a visual solubility method 1Trade name for "caprylocaproyl macrogolglycerides"
Two important parameters for defining optimal delivery of molecules across the skin include: (a) amount of drug in solution in the formulation; and (b) use of penetration enhancers to improve delivery.
In selecting solubility or penetration enhancers, the following factors need to be kept in mind:
(a) safety and tolerability of the agent
(b) non-irritancy
(c) no pharmacological effect of its own
(d) compatibility with the active pharmaceutical ingredient (e) regulatory acceptance (GRAS-listed or on the Inactive Ingredients list)
(f) effectiveness of the agent in either increasing solubility or penetration
Note, that in the choice of these agents, it is possible that one may function both as a solubilizer as well as a penetration enhancer.
Table 27 lists some formulations that were prepared for flux studies. Formulations prepared for the compound of formula Ia* used GRAS-listed excipients. Formulations were adapted to ensure that all drug is in solution in its respective phase. For this study, the drug concentration was capped at 1 % and 2%. A series of solubility screening studies were completed prior to the formulation stage to determine the concentration of the compound of formula Ia* that could be dissolved in pure solvent, as well as in solvent: water systems. PEG200, propylene glycol, benzyl alcohol and transcutol afforded the good solubility, and hence were used in the formulations. Each of the formulations also included the use of known penetration enhancers.
Table 27
Formulations of Compound of Formula Ia* Prepared for First Skin Flux
Studies
Each of these formulations was studied in an in vitro skin flux experiment. Briefly, abraded dermatomed human abdominal skin was placed across two static Franz diffusion cells. The skin was tape-stripped to reflect the wound indication. Formulation was placed in the "donor" cell, and samples taken from the "receptor" cell at predetermined time intervals over a 24-hour period. Samples were analyzed using an LC-MS-MS method, and flux (permeation rate) calculated over 24 hours. The resulting data is shown in Figure 1. The flux of the compound of formula Ia* ranged from below the level of quantitation to 2.77 ng/(cm2*hr) from 0-4 hours exposure, 0.18 to 4.28 ng/(cm2*hr) from 4-24 hours exposure, and 0.19 to 4.37 ng/(cm2*hr) from 0-24 hours exposure. The highest drug flux over 24 hours was observed from the dual enhancer cream on the abraded skin (4.37 ng/(cm2*hr)). The ointment formulation produced the next largest flux rate (0.58 ng/(cm2*hr)). The hydrophilic ointment produced comparable flux rates on both the intact skin and the abraded skin (0.19 ng/(cm2*hr) and 0.21 ng/(cm2*hr), respectively). The cumulative percent of the applied dose of the compound of formula Ia* penetrating the skin over the 24 hour duration of exposure ranged from 0.009% to 0.223%. The highest percent of applied dose penetrating the skin was observed with the dual enhancer cream on the abraded skin, 0.223%.
Based on the promising results of the first skin flux studies, additional formulations were prepared to further optimize the delivery of the compound of formula Ia* and the results are summarized in Table 28.
Table 28 lists some formulations exemplified in this invention together with flux data. The protocol for conducting the in vitro skin flux is briefly as follows. Abraded dermatomed human abdominal skin was placed across two Franz diffusion cells. The skin was tape-stripped to reflect the wound indication. The formulation was placed in the donor cell, and samples were taken from the receptor cell at predetermined time intervals over a 24-hour period. Samples were analyzed using an LC-MS-MS method, and flux (permeation rate) calculated over 24 hours.
Table 28
Percutaneous Flux Through Human Skin of Compound Ia* Topical Formulations
* PG: Propylene Glycol; PEG200: polyethylene glycol
Target Flux: Intact Skin: 200 ng/cm2/hr; Dermis alone (or abraded): 1000 ng/cm2/hr
The foregoing examples and information has been provided to illustrate the invention, not limit it. What is reserved to the inventors is to be measured by the claims hereinafter.

Claims

What is claimed is:
1. A method of inhibiting excess scar formation on skin comprising the administration of a vitronectin receptor antagonist in a pharmaceutically acceptable formulation to a mammal in need thereof.
2. The method of claim 1 wherein said mammal is a human.
3. The method of claim 1 or 2, wherein said administration is topical.
4. The method of claims 1 , 2, or 3, wherein the vitronectin receptor antagonist comprises a compound of formula I or II:
wherein:
R is H, C-I-6 alkyl, Ar, Het, or C1-6alkylaryl;
R is R , A-Co-4 alkyl, A-C2-4alkenyl, A-C2-4alkynyl, A-C3-4oxoalkenyl, A-C3-4θxoalkynyl, A-C-] _4aminoalkyl, A-C3_4aminoalkenyl, or A-C3_4aminoalkynyl, unsubstituted or substituted by any accessible combination of one or more of R1 0 or
R7;
A is H1 C3-6cycloalkyl, Het or Ar;
R7 is -COR8, -COCR'2R9, -C(S)R8, -S(O)mOR', -S(O)mNR'R", -PO(OR1), -PO(OR')2, -NO2, or tetrazolyl; each R8 is independently -OR1, -NR1R", -NR'SO2R\ -NR1OR1, or -OCR'2CO(O)R';
R9 is -OR1, -CN, -S(O)1-R1, -S(0)mN(R')2, -C(O)R1, C(0)N(R')2. or -CO2R1; R10 is H, halo, -OR1 1 , -CN, -NR1R1 1 , -NO2, -CF3, CF3S(O)n -CO2R1, -C0N(R')2, A-Co-6alkyl-ι A-Ci -βoxoalkyl-, A-C2-6alkenyI-, A-C2-6alkynyl-, A-Crj-βalkyloxy-, A-Cn-βalkylamino- or A-Crj-6alkyl-S(O)r;
R1 1 is R1, -C(O)R1, -C(O)N(R')2, -C(O)OR1, -S(O)mR\ or -S(0)mN(R')2;
W is -(CHRg)a-U-(CHRg)b-;
U is absent or is CO, CRS2, CC=CRQ2), S(OJi0 O, NR9, CR9OR9, CR9(ORk)CRg2, CR92CR9(ORk), C(O)CR92, CR92C(O), CONR", NR'CO, OC(O), C(O)O1 C(S)O, OC(S), C(S)NRQ, NR9C(S), S(O)2NRg, NRgS(O)2 N-N, NRgNRg, NR9CR92, CR92NRg, CR92O, OCR92, C≡C or CRg=CRS;
G is NRe, S or 0;
Rg is H, C-μgalkyl, Cs-ycycloalkyl-Co-βalkyl or Ar-Co-βalkyl; Rk is R9, -C(O)R9, or -C(O)ORf; R' is is H, C-|_6alkyl, Het-Co_6alkyl, Cs-ycycloalkyl-Cn-ealkyl, Ar- Cυ-6alkyl, or C-| .galkyl substituted by one to three groups chosen from the group consisting of halogen, CN, NR92, OR9, SR9, CO2RS, and CON(RS)2;
Rf is H, C-μβalkyl or Ar-Cn-6alkyl; Re is H, C-| .galkyl, Ar-Cn-βalkyl, Het-Cn-6alkyl, Cs-ycycloalkyl-Crj-ealkyl, or
(CH2)kCO2Rg;
Rb and Rc are independently selected from the group consisting of H, C-| . galkyl, Ar-Cg.galkyl, Het-Cn-βalkyl, C3-6cycloalkyl-Co_6alkyl, halogen, CF3, OR^,
S(O)kRf, CORf, NO2, N(Rf)2i CO(NRf)2, and CH2N(Rf)2, or Rb and Rc are joined together to form a five or six membered aromatic or non-aromatic carbocyclic or heterocyclic ring, unsubstituted or substituted by up to three substituents chosen from the group consisting of halogen, CF3, C-^alkyl, 0Rf, S(O)kRf, CORf, CO2Rf, OH, NO2, N(Rf)2] C0(NRf)2, CH2N(Rf)2, and methylenedioxy;
Q1 , Q2, Q3 and Q4 are independently N or C-RY, provided that no more than one of Q1 , Q2, Q3 and Q4 is N;
R1 is H, Ci -6alkyl, Ar-Crj-βalkyl or Cs-θcycloalkyl-Co-βalkyl;
R" is R', -C(O)R' or -C(O)OR1;
R'" is H, C-| .galkyl, Ar-Cn-βalkyl, Het-Crj-6alkyl, Cs-Qcycloalkyl-Cn-ealkyl, halogen, CF3, 0Rf, S(O)kRf, CORf, NO2, N(Rf)2) CO(NRf)2, or CH2N(Rf)2; RY is H, halo, -0R9, -SR9, -CN, -NR9Rk, -NO2, -CF3, CF3S(O)n -CO2R9,
-C0R9 or -CONRS2, or Ci -βalkyl unsubstituted or substituted by halo, -ORS, -SR9, - CN, -NR9R", -NO2, -CF3, R1S(O)n -CO2R9, -COR9 or -CONR92; a is 0, 1 or 2; b is O, 1 or 2; k is O, 1 or 2; m is 1 or 2; r is O, 1 or 2; s is O, 1 or 2; u is O or 1 ; and v is O or 1 , or a compound of formula II;
wherein Ai is C or N;
E is a five- or six-membered heteroaromatic or six-membered aromatic ring unsubstituted or substituted by R3* or R4*;
X1-X2 is CHR1*-CH, CR1 *=C, NR1 *-CH, S(O)U*-CH or O-CH; X3 is CR5*R5'*, NR5*, S(O)U* or O; R1* is H, d-e alkyl, Ar, Het, d-ealkylaryl;
R"* is R1*, -C(O)R1* or -C(O)OR5*; R'"* is C-| -6alkyl, C3-7cycloalkyl-Co-4alkyl or Ar-Co-4alkyl;
R1 * is H, Ci -6alkyl, or Ar-Crj-4alkyl; R2* is -OR1*, -NR'*R"*, -NR'*SO2R'"*, -NROR1*, -OC(R'*)2C(O)OR'*, - OC(R'*)2θC(O)-R'*, -OC(R'*)2C(O)N(R'*)2, CF3 or COC(R'*)2R2'*;
R21* is -OR1*, -CN, -S(O)r*R'*, S(O)2N(R'*)2, -C(O)R1*, C(O)N(R'*)2 or - CO2R1*;
R5* and R51* are independently H, C-|-6alkyl, Cs-ycycloalkyl-Co^alkyl or Ar- Cn-4alkyl; R6* is W-(C(R'*)2)q*-Z*-(CR'*Ri 0*)r*-U*-(C(R'*)2)s*-V*- or W'*-(C(R1*)2)q*-
U*-(C(R'*)2)s*-;
R3*. R4* and R7* are independently H, halo, -OR12*. -SR12*. -CN1 - NR'*R12*, -NO2, -CF3, CF3S(O)r*-, -CO2R1*, -CON(R1^1 Ri4*-Cθ-6a|kyl-, R14*- Ci-6oxoalkyl, Ri4*-C2_6alkenyl-, Ri4*o2-6alkynyl, Ri4*-Co-6alkyloxy-, R14*-CQ. 6alkylamino or Ri4*-Co-6alkyl-S(0)r*-;
R8* is R1*, C(O)R1*, CN, NO2, Sθ2R"*or C(O)OR5*;
R9* is R1*, -CF3, -SR1*, or -OR'*;
R1O* is H, Ci -4alkyl or -NR'*R"*;
R12* is R1*, -C(O)R1*, -C(O)N(R'*)2, -C(O)ORS*, -S(O)m*R'* or S(O)2N(R'*)2; R14* is H, C3-6cycloalkyl, Het or Ar;
R15* is H, C-|-ioalkyl, Cs-ycycloalkyl-Crj-salkyl or Ar-Crj-δalkyl;
U* and V* are absent or are CO, C(R'*)2, C=C(Ri 5*)2, S(O)n*, O, NR15*,
CR15'*OR15*, CR'*(OR"*)CR'*2, CR'*2CR'*(OR"*)J C(O)C(R'*)2, C(R15*)2C(O), CONR15*, NR15*CO, OC(O), C(O)O, C(S)O, OC(S), C(S)NRi 5*, NR15*C(S),
SO2NR15*, NR15*SO2, N=N, NR15*NR15*, NR15*C(R15*)2I NR15*C(R15*)2I
C(R15*)2O, OC(Ri 5*)2, G=C1 CR15*_-CR15*, Het, or Ar, provided that U* and V* are not simultaneously absent;
W* is R'*R"*N-, R'*R"*NR'*N-, R^R'^NR^NCO-, R'*2NR'*NC(=NR'*)-, R'ONR'*C(=NR'*)-,
)
W* is
Q* is NR1*, O or S; Ra* is H, C-|-6alkyl, Ar-Co-6alkyl, Het-Co-βalM. or Cs-ecycloalkyl-Co-βalkyl, halogen, OR1*, SR1 *, COR1*, OH, N02, N(R1 *)2, CO(NR1*)2, or CH2N(R1*)2;
Rb* and Rc* are independently selected from the group consisting of H, Ci- δalkyl, Ar-Co-6a'W. Het-Co-βa'kyl. or C3-6cycloalkyl-Cn-6a|kyl> halogen, OR-I*, SR1 *, COR1 *, OH, N02, N(Ri *)2, CO(NRi *)2, CH2N(R1 *)2, or Rb* and RC* are joined together to form a five or six membered aromatic non-aromatic ring, optionally substituted by halogen, Ci-4alkyl, OR1*, SR1*, COR1*, OH, NO2, N(R1 *)2, CO(NRi *)2J CH2N(R1*)2, CN, or R"*R'*NC(=NR'*)-;
X* is N=CR1, C(O) or O; Y* is absent, S or O;
Z* is (CH2)t*. Het, Ar or C3_7cycloalkyl;
M* is 1 or 2;
N* is 0, 1 , 2, or 3; q* is θ, 1 , 2, or 3; r* is 0, 1 or 2; s* is 0, 1 or 2; t* is 0, 1 or 2; u* is 0, 1 or 2; v* is O or 1 ; and w* is 0 or 1 ; or or a pharmaceutically acceptable salt or solvate thereof.
5. The method of claim 4, wherein the compound of formula I is Ia
Ia
wherein R is H, Ci.6alkyl, Ar, Het, or C1-6alkylaryl; or a pharmaceutically acceptable salt or solvate thereof.
6. The method of claim 5, wherein R is H.
7. The method of claim 4, wherein the compound of formula Il is Na
Na wherein R2* is H, d^alkyl, Ar, Het, or C1-6alkylaryl; or a pharmaceutically acceptable salt or solvate thereof.
8. The method of claim 7, wherein R2* is H.
9. The method according to any one of claims 1 through 8, wherein the excessive scarring is hypertrophic.
10. A formulation suitable for the topical administration of a compound of formula I or II,
I wherein:
R is H, Gi-salkyl, Ar, Het, C^alkylaryl
R is R , A-Co-4 alkyl, A-C2-4alkenyl, A-C2-4alkynyl, A-C3-4θxoalkenyl, A-C3_4oxoalkynyl, A-C-] ^aminoalkyl, A-C3_4aminoalkenyl, or A-C3_4aminoalkynyl, unsubstituted or substituted by one or more of R1 ° or R7; A is H, C3-6cycloalkyl, Het or Ar;
R7 is -CORδ, -COCR'2R9, -C(S)R8, -S(O)mOR', -S(O)mNR'R", -PO(OR1), -PO(OR')2, -NO2, or tetrazolyl; each R8 is independently -OR1, -NR1R", -NR'SCfcR1, -NR1OR1, or
-OCR'2CO(O)R';
R9 is -OR', -CN1 -S(O)1-R1, -S(O)mN(R1)2, -C(O)R', C(O)N(R1)2, or -CO2R"; R1O is H, halo, -OR1 1 , -CN, -NR1R1 1 , -NO2, -CF3, CF3S(O)r, -CO2R1, -CON(R')2, A-Co-6alkyl-, A-C-|-6θxoalkyl-, A-C2-6alkenyl-, A-C2-6alkynyl-, A-Co-6alkyloxy-, A-Crj-θalkylamino- or A-Co-6alkyl-S(0)r;
R1 1 is R1, -C(O)R1, -C(O)N(R')2, -C(O)OR1, -S(O)mR\ or -S(0)mN(R')2;
W is -(CHRg)a-U-(CHRg)b-;
U is absent or is CO, CRS2, C(=CR92), S(O)I0 O, NR9, CR9OR9, CRg(ORk)CRS2, CRg2CR9(ORk), C(O)CR92, CRg2C(O), CONR', NR'CO, OC(O)1 C(O)O, C(S)O, OC(S), C(S)NRg, NR9C(S), S(O)2NR9, NRgS(O)2 N=N, NR9NR9, NR9CR92, CRg2NRg, CR92O, OCRg2, C≡C Or CRg=CRg; G is NRe, S or O;
R9 is H, C-μgalkyl, Het-Crj.galkyl, C3_7cycloalkyl-Crj-galkyl or Ar-Crj-galkyl;
Rk is R9, -C(0)R9, or -C(O)ORf ;
R' is is H, C-| .galkyl, Het-Cø-galkyl, Cs-zcycloalkyl-Co-galkyl, Ar- Crj_galkyl, or C-| .galkyl substituted by one to three groups chosen from the group consisting of halogen, CN, NRS2, OR9, SR9, CO2RS, and CON(RS)2; Rf is H, C-j_6alkyl or Ar-Co-6alkyl;
Re is H, C-| .galkyl, Ar-Cn.galkyl, Het-Co-galkyl, Cs-ycycloalkyl-Crj-galkyl, or ' (CH2)kCO2R9; RD and Rc are independently selected from the group consisting of H, C-| . galkyl, Ar-Crj-galkyl, Het-Crj-galkyl, Cs-gcycloalkyl-Crj-galkyl, halogen, CF3, OR*,
S(O)kRf, CORf, NO2, N(Rf)2; CO(NRf)2, CH2N(Rf)2; or Rb and Rc are joined together to form a five or six membered aromatic or non-aromatic carbocyclic or heterocyclic ring, unsubstituted or substituted by up to three substituents chosen from the group consisting of halogen, CF3, Chalky], ORf, S(O)kRf, C0Rf, C02Rf, OH, NO2, N(R^)2, CO(NRf)2, CH2N(Rf)2 and methylenedioxy;
Q1 , Q2, Q3 and Q^ are independently N or C-Ry, provided that no more than one of Q1 , Q2, Q3 and Q4 is N;
R' is H, Ci -galkyl, Ar-Crj-6alkyl or C3-gcycloalkyl-Crj-6alkyl; R" is R1, -C(O)R' or -C(O)OR1;
R'" is H, C-| .galkyl, Ar-Crj-galkyl, Het-Crj-galkyl, or C3-gcycloalkyl-Co-galkyl, halogen, CF3, 0Rf, S(0)kRf, C0Rf, NO2, N(Rf)2j C0(NRf)2, CH2N(Rf)2;
Ry is H, halo, -0R9, -SR9, -CN, -NR9RI<, -NO2, -CF3, CF3S(O)Γ, -CO2RS, -CORS or -CONRS2, or Ci -galkyl unsubstituted or substituted by halo, -ORS, -SRS, - CN, -NRSR", -NO2, -CF3, R1S(O)1--, -CO2R9, -CORS or -CONRS2; a is 0, 1 or 2; b is 0, 1 or 2; k is O, 1 or 2; m is 1 or 2; r is 0, 1 or 2; s is O, 1 or 2; u is 0 or 1 ; and v is 0 or 1 ; or a compound of formula Il
wherein
Ai is C or N;
E is a five- or six-membered heteroaromatic or six-membered aromatic ring optionally substituted by R3* or R4*;
X1-X2 is CHR1*-CH, CR1*=C, NR1*-CH, S(O)U*-CH or O-CH; X3 is CR5*R5'*, NR5*, S(O)U* or O;
R1* is H, Ci-6alkyl, Ar, Het, d^alkylaryl;
R"* is R'*, -C(O)R'* or -C(O)ORs*; R'"* is Cl -βalkyl, C3-7cycloalkyl-Co-4alkyl or Ar-Co-4alkyl;
R1* is H, Ci-6alkyl, or Ar-Co-4alkyl;
R2* is -OR1*, -NR'*R"*, -NR1*Sθ2R'"*, -NROR1*, -OC(R'*)2C(O)OR'*, - OC(R'*)2θC(O)-R'*, -OC(R'*)2C(O)N(R'*)2, CF3 or COC(R"*)2R2'*;
PS"* is -OR1*, -CN1 -S(O)r*R'*, S(O)2N(R'*)2, -C(O)R1*, C(O)N(R'*)2 or - CO2R1*;
R5* and R5'* are independently H, C-| -6alkyl, C3-7cycloalkyl-Cfj-4alkyI or Ar- Co-4alkyl;
R6* is W-(C(R'*)2)q*-Z*-(CR'*Ri 0*)r*-U*-(C(R'*)2)s*-V*- or W'*-(C(R'*)2)q*" U*-(C(R'*)2)s*-; R3*, R4* and R7* are independently H, halo, -OR12*, -SR12*, -CN, -
NR-*R12*, -NO2, -CF3, CF3S(O)r*-, -CO2R1*, -CON(R1*)2, Ri4*-Cθ-6a|kyl-, R14*. C-|-6θxoalkyl. Ri4*-C2-6alkenyl-, Ri4*-C2-6alkynyl, Ri4*_Co-6alkyloxy-, R14*-CO- βalkylamino or Ri4*-Co-6alkyl-S(0)r*-;
R8* is R1*, C(O)R1*, CN, NO2, Sθ2R'*or C(O)OR5*; R9* is R1*, -CF3, -SR1*, or -OR1*;
R1O* is H, Ci-4alkyl or -NR"*R"*;
R12* is R'*, -C(O)R1*, -C(O)N(R'*)2, -C(O)OR5*, -S(O)m*R'* or S(O)2N(R'*)2;
R14* is H, C3-6cycloalkyl, Het or Ar; R15* is H, Cl -1 rjalkyl, Cs-ycycloalkyl-Crj-salkyl or Ar-Crj-8alkyl;
U* and V* are absent or CO1 C(R'*)2, C=C(Ri 5*)2, S(O)n*, O, NR15*, CR15'*OR15*, CR'*(OR"*)CR'*2, CR'*2CR'*(OR"*), C(0)C(R'*)2, C(R15*)2C(O), CONR15*, NR15*CO, OC(O), C(O)O, C(S)O, OC(S), C(S)NRi 5*, NR15*C(S), SO2NR15*, NR15*SO2, N=N, NR15*NR15*, NR15*C(R15*)2, NR15*C(R15*)2, C(R15*)2O, OC(Ri 5*)2> C≡C, CR15*=CR15*, Het, or Ar, provided that U* and V* are not simultaneously absent;
W* is R'*R"*N-, R'*R"*NR"*N-, R^R'^NR^NCO-, R'*2NR'*NC(=NR'*)-, R1ONR^Ct=NR1*)-,
W* is
Q* is NR1*, O or S;
Ra* is H, C-i-βalkyl, Ar-Co-βalkyl, Het-Co-βalkyl, Cs-βcycloalkyl-Co-ealkyl, halogen OR1 *, SR1*, COR1*, OH1 N02, N(R1*)2, CO(NRi *)2i or CH2N(Ri *)2; Rb* and Rc* are independently selected from the group consisting of H, C-|. βalkyl, Ar-Crj-6alkyl, Het-Co-6alkyl, Cs-ecycloalkyl-Co-βalkyl, halogen, OR-I*, SR1*, COR1*, OH, NO2, N(R1*)2, CO(NRi *)2, CH2N(Ri *)2; Or Rb* and RC* are joined together to form a five or six membered aromatic non-aromatic ring, unsubstituted or substituted by halogen, Ci^alkyl, OR1*, SR1 *. COR1*, OH, NO2, N(R1*)2, CO(NRi *)2, CH2N(Ri *)2, CN1 or R"*R'*NC(=NR'*)-;
X* is N=CR1, C(O) or O;
Y* is absent, S or O;
Z* is (CH2)t*, Het, Ar or C3-7cycloalkyl;
M* is 1 or 2; N* is O, 1 , 2, or 3; q* is θ, 1, 2, or 3; r* is 0, 1 or 2; s* is O1 1 or 2; t* is O, 1 or 2; u* is O, 1 or 2; v* is O or 1 ; and w* is O or 1 ; or a pharmaceutically acceptable salt or solvate thereof, wherein: the formulation comprises from about 0.01 % to 50% w/w of the compound of formula I or Il and from about 0.5% to 99% of one or more penetration enhancers.
11. The formulation of claim 10, wherein said compound of formula I is Ia,
Ia
wherein R is H, C1-Balkyl, Ar, Het, or (^alkylaty!; or a pharmaceutically acceptable salt or solvate thereof, and the compound of formula Il is Ha,
Ha wherein R2* is H1 C1-6alkyl, Ar, Het, of Ci-6alkylaryl; or a pharmaceutically acceptable salt or solvate thereof.
12. The formulation of claim 11 , wherein R and R2* are each hydrogen.
13. The formulation according to any one of claims 10 through 12, wherein the compound of formula I, II, Ia1 or Na, comprises from about 0.01% to 10% w/w of the formulation.
14. The formulation according to any one of claims 10 through 13, wherein the one or more penetration enhancers is present in from about 0.5% to 40% w/w of the formulation.
15. The formulation according to any one of claims 10 through 14, wherein said one or more penetration enhancers is selected from the group consisting of propylene glycol, benzyl alcohol, polyethylene glycols, dimethyl isorbide, diethylene glycol monomethyl ether, macrogol 2 stearyl ethers, polyoxyl stearyl ethers, polyoxyl lauryl ethers, polyoxyl cetyl ethers, laurocapram, and caprylocaproyl macrogol-8 glycerides, or combinations thereof.
16. The formulation according to claim 15, wherein said one or more penetration enhancers comprises propylene glycol.
17. The formulation according to any one of claims 10 through 15, wherein said one or more penetration enhancers comprises at least one surfactant.
18. The formulation according to any one of claims 10 through 17, wherein said formulation has a pH of greater than about 7.
19. The formulation of claim 18, wherein said formulation has a pH of greater than 8.
20. The formulation of claim 19, wherein said formulation has a pH of from about 8.5 to 9.5.
21. The formulation according to any one of claims 10 through 19, further comprising from about 1 % to 45% w/w of a buffer having a pH in the range of from 8 to 11.
22. The formulation according to any one of claims 10 through 21 , further comprising from about 25% to 75% w/w of one or more waxes, ointments, or bases, or combinations thereof.
23. The formulation according to any one of claims 10 through 22, further comprising from about 4% to 12% w/w of one or more emollients.
24. The formulation according to any one of claims 10 through 23, further comprising from about 0.5% to 10% w/w of one or more surfactants.
25. The formulation according to any one of claims 10 through 24, further comprising from about 0.001 % to 2% of one or more antioxidants.
26. The formulation of any one of claims 10 through 12, wherein said formulation comprises: from about 0.05% to 5% of a compound of formula I, II, Ia, or Ha; from about 40% to 60% w/w of one or more waxes, ointments, or bases, or combinations thereof; from about 6% to 10% w/w of one or more emollients; from about 1.0% to 25% of one or more penetration enhancers; from about 0.01% to 1% of one or more antioxidants; and from about 5% to 35% w/w of a pH 9-11 buffer.
27. The formulation of claim 26, wherein said formulation comprises: from 0.1 % to 2% w/w of the compound of formula I, II, Ia, or Ha; from about 40% to 60% w/w of one or more waxes, ointments, or bases, or combinations thereof; from about 6% to 10% w/w of one or more emollients; from about 4.0% to 18% of one or more penetration enhancers; from about 0.01 % to 0.5% of one or more antioxidants; and from about 10% to 30% w/w of a pH 9.5-10.5 buffer.
28. The formulation of claim 27, wherein said formulation comprises: from about 0.1 % to 2% w/w of the compound of formula I, II, Ia, or Ha; from about 50% to 60% w/w of one or more waxes, ointments, or bases, or combinations thereof; from about 7% to 9% w/w of one or more emollients; from about 10.0% to 18% of one or more penetration enhancers; from about 0.01 % to 0.2% of one or more antioxidants; and from about 20% to 28% w/w of a pH 9.5-10.5 buffer.
29. The formulation according to claim 28, wherein said formulation comprises: from about 0.1 -1.0% of the compound of formula I, II, Ia, or Na; from about 45% to 55% petrolatum; from about 6% to 10% mineral oil; from about 3% to 8% polyoxyl stearyl ether; from about 0.01 % to 0.1% butylated hydroxyanisole; and from about 20% to 28% w/w borate buffer with a pH about 10.
30. The formulation of any one of claims 26 through 29 containing a compound of formula Ia or Ha, wherein R and R2* are each hydrogen.
31. A method of preventing excessive scarring comprising the topical administration of a formulation of any one of claims 10 through 30, wherein said administration is to a mammal's skin, wherein said skin has been cut, split, torn, or otherwise injured in such a way that excessive scarring upon healing might result.
32. The method of claim 31 , wherein the mammal is a human.
33. The method of claim 31 or 32, wherein said administration comprises repeated applications.
34. The method of any one of claims 31 through 33, wherein said scarring is hypertrophic.
EP05854851A 2004-12-21 2005-12-20 Methods and formulations Withdrawn EP1841406A4 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US63782404P 2004-12-21 2004-12-21
PCT/US2005/046204 WO2006069079A2 (en) 2004-12-21 2005-12-20 Methods and formulations

Publications (2)

Publication Number Publication Date
EP1841406A2 true EP1841406A2 (en) 2007-10-10
EP1841406A4 EP1841406A4 (en) 2008-06-25

Family

ID=36602271

Family Applications (1)

Application Number Title Priority Date Filing Date
EP05854851A Withdrawn EP1841406A4 (en) 2004-12-21 2005-12-20 Methods and formulations

Country Status (6)

Country Link
EP (1) EP1841406A4 (en)
JP (1) JP2008524334A (en)
AR (1) AR052823A1 (en)
PE (1) PE20060870A1 (en)
TW (1) TW200635902A (en)
WO (1) WO2006069079A2 (en)

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UA60311C2 (en) * 1996-10-02 2003-10-15 Смітклайн Бічам Корпорейшн Vitronectin receptor antagonists
UA71586C2 (en) * 1998-12-04 2004-12-15 Smithkline Beecham Corp A vitronectin receptor antagonist
AU747503B2 (en) * 1999-02-03 2002-05-16 Merck & Co., Inc. Benzazepine derivatives as alpha-V integrin receptor antagonists
KR20030087069A (en) * 2001-04-10 2003-11-12 스미스클라인 비참 코포레이션 Method of Inhibiting Adhesion Formation

Also Published As

Publication number Publication date
WO2006069079A2 (en) 2006-06-29
AR052823A1 (en) 2007-04-04
JP2008524334A (en) 2008-07-10
EP1841406A4 (en) 2008-06-25
PE20060870A1 (en) 2006-08-16
TW200635902A (en) 2006-10-16
WO2006069079A3 (en) 2007-04-19

Similar Documents

Publication Publication Date Title
US12403091B2 (en) Delivery system
ES2225926T3 (en) COMPOSITIONS TO POWER THE PENETRATION OF PHARMACOS USING PERMEATION PROMOTERS.
FI119755B (en) Use of an unsaturated fatty alcohol
US20120295914A1 (en) Combination of adrenergic receptor agonist alpha-1 or alpha-2, preferably brimonidine with fillers, preferably hyaluronic acid
SK14762003A3 (en) A skin permeable composition comprising selectively cyclooxygenase-2 inhibiting and monohydric alcohol
AU2010336018B2 (en) Carrier composition
JP2014098046A (en) Diclofenac novel nonaqueous solution for external use and process for preparing the same
AU2016271468B2 (en) Topical formulations for delivery of hedgehog inhibitor compounds and use thereof
JP4987209B2 (en) Use of biguanide derivatives for the manufacture of pharmaceuticals with scarring action
WO1999033458A1 (en) Medicinal composition for percutaneous administration
KR20100099191A (en) Pre-surgical treatment
TW200401637A (en) Use of thio-oxindole derivatives in treatment of skin disorders
KR20000048944A (en) 1,3-Bis-(N-lactamyl)propanes and Their Pharmaceutical and Cosmetic Use
JP2021529811A (en) Topical detomidine preparation
CN120661657A (en) Methods and compositions for treating peripheral neuropathy
WO2021222009A1 (en) Clobazam transdermal delivery system and uses thereof
US20050096371A1 (en) Topical pharmaceutical compositions
KR101981206B1 (en) Preparation for enhanced transdermal absorption of medicine
CN113941002B (en) Slow-release drug delivery system for small-molecule drugs
EP1841406A2 (en) Methods and formulations
US20060182790A1 (en) Dermal medicaments application enhancer
DK2632468T3 (en) THERAPEUTIC COMPOSITIONS FOR SYMMETRIC DIABETIC POLYNEuropathy
CA2869377A1 (en) Fulvestrant formulations
EP1633323B1 (en) Ternary eutectic mixtures of local anesthetics
US20080075745A1 (en) Topical pharmaceutical compositions containing ciclopirox or a pharmaceutically acceptable salt thereof

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20070718

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA HR MK YU

RIC1 Information provided on ipc code assigned before grant

Ipc: A01N 25/00 20060101ALI20071108BHEP

Ipc: A01N 65/00 20060101AFI20071108BHEP

RAX Requested extension states of the european patent have changed

Extension state: HR

Payment date: 20070718

A4 Supplementary search report drawn up and despatched

Effective date: 20080526

17Q First examination report despatched

Effective date: 20080721

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20081202