EP1841406A2 - Methods and formulations - Google Patents
Methods and formulationsInfo
- 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- Withdrawn
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
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WO1998014192A1 (en) * | 1996-10-02 | 1998-04-09 | Smithkline Beecham Corporation | Vitronectin receptor antagonists |
WO2000033838A1 (en) * | 1998-12-04 | 2000-06-15 | Smithkline Beecham Corporation | Vitronectin receptor antagonist |
WO2002083125A1 (en) * | 2001-04-10 | 2002-10-24 | Smithkline Beecham Corporation | Method of inhibiting adhesion formation |
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EP1150965A4 (en) * | 1999-02-03 | 2002-05-15 | Merck & Co Inc | Benzazepine derivatives as alpha-v integrin receptor antagonists |
-
2005
- 2005-12-20 TW TW094145347A patent/TW200635902A/en unknown
- 2005-12-20 EP EP05854851A patent/EP1841406A4/en not_active Withdrawn
- 2005-12-20 AR ARP050105363A patent/AR052823A1/en unknown
- 2005-12-20 JP JP2007548398A patent/JP2008524334A/en not_active Withdrawn
- 2005-12-20 WO PCT/US2005/046204 patent/WO2006069079A2/en active Application Filing
-
2006
- 2006-01-03 PE PE2006000024A patent/PE20060870A1/en not_active Application Discontinuation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998014192A1 (en) * | 1996-10-02 | 1998-04-09 | Smithkline Beecham Corporation | Vitronectin receptor antagonists |
WO2000033838A1 (en) * | 1998-12-04 | 2000-06-15 | Smithkline Beecham Corporation | Vitronectin receptor antagonist |
WO2002083125A1 (en) * | 2001-04-10 | 2002-10-24 | Smithkline Beecham Corporation | Method of inhibiting adhesion formation |
Non-Patent Citations (1)
Title |
---|
See also references of WO2006069079A2 * |
Also Published As
Publication number | Publication date |
---|---|
EP1841406A4 (en) | 2008-06-25 |
AR052823A1 (en) | 2007-04-04 |
WO2006069079A3 (en) | 2007-04-19 |
PE20060870A1 (en) | 2006-08-16 |
WO2006069079A2 (en) | 2006-06-29 |
JP2008524334A (en) | 2008-07-10 |
TW200635902A (en) | 2006-10-16 |
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