# Patent

## Title
Stabilization of retinoid compounds

## Abstract

The present invention relates to a method of administering a compound of Formula I: 




wherein

    
    
        R1 is hydrogen or C1-6-alkyl;
        R2 is C1-6-alkyl or adamantyl;
        R3 is C1-6-alkyl or hydroxy; or
        R2 and R3 taken together are —(CR6R7)n—;
        R4 is C2-8-alkyl, C2-8-alkenyl, C2-8-alkynyl, —OCH2R5 or C2-8-alkanoyl, or hydrogen when R3 is hydroxy;
        R5 is C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl;
        R6 and R7 are hydrogen or C1-6-alkyl;
        Y is oxygen or sulfur; and
        n is 3, 4, or 5,
        or a pharmaceutically acceptable salts of carboxylic acid of formula I,
        wherein said method comprises the step of admixing said compound in solid form with a topical carrier to form a topical formulation within seven days prior to first topical administration of said compound.

## Background
CROSS-REFERENCE
This application claims priority from provisional application Ser. No. 60/262,687 filed on Jan. 19, 2001.


FIELD OF THE INVENTION
The present invention relates to the topical delivery of retinoid compounds.
BACKGROUND OF THE INVENTION
Retinoic acid is a retinoid sold both for the topical treatment of acne (Retin-A®, Ortho Dermatological, Skillman, N.J.) and for the topical treatment of fine wrinkles, mottled hyperpigmentation, and tactile roughness of facial skin (Renova®, Ortho Dermatological). The compound is formulated into a variety of topical gels, creams, and solutions.
U.S. Pat. No. 5,726,191 recently reported a new class of retinoids. According to the '191 Patent, these compounds can be topically administered in ointments, tinctures, creams, solutions, lotions, sprays, and suspensions. Applicants, however, have found that while members of this class of compounds were very potent in binding to the retinoid receptor, they are chemically unstable in topical formulations.
In fact, applicants tested Compound I, a compound from this class, in a vast array of topical liquid or semisolid pharmaceutical formulations. None of these formulations, however, were capable of sufficiently stabilizing the compound when stored at room temperature (between 20 to 30° C.), thus, inhibiting the ability to market the compound in a topical formulation.
The present invention relates to stabilizing this new class of retinoids in a manner suitable for topical administration.
SUMMARY OF THE INVENTION
In one aspect, the invention features a method of administering a compound of Formula I (defined herein), wherein the method includes the step of admixing the compound in solid form with a topical carrier to form a topical formulation within seven days prior to first topical administration of the compound.
In another aspect, the invention features a kit comprising two chambers, wherein the first chamber contains a compound in solid form and the second chamber contains a topical carrier in an amount capable of dissolving or dispersing said compound where the compound is of Formula I.
Other features and advantages of the present invention will be apparent from the detailed description of the invention and from the claims.
DETAILED DESCRIPTION OF THE INVENTION
It is believed that one skilled in the art can, based upon the description herein, utilize the present invention to its fullest extent. The following specific embodiments are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. Also, all publications, patent applications, patents, and other references mentioned herein are incorporated by reference.
In one aspect, the present invention relates to a method of administering a compound of Formula I 




wherein

    
    
        R1 is hydrogen or Cl-6-alkyl;
        R2 is C1-6-alkyl or adamantyl;
        R3 is C1-6-alkyl or hydroxy; or
        R2 and R3 taken together are —(CR6R7)n—;
        R4 is C2-8-alkyl, C2-8-alkenyl, C2-8-alkynyl, —OCH2R5 or C2-8-alkanoy, or hydrogen when R3 is hydroxy;
        R5 is C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl;
        R6 and R7 are hydrogen or C1-6-alkyl;
        Y is oxygen or sulfur; and
        n is 3, 4, or 5,

or a pharmaceutically acceptable salts of the carboxylic acid of formula I.

    
    


The notations “C1-6”, “C2-6”, and “C2-8” used herein stand for groups with from 1 to 6, from 2 to 6 and from 2 to 8 carbon atoms, respectively. Alkyl residues can be straight-chain or branched. The alkyl residues of R1 may be straight-chain such as methyl, ethyl, propyl, butyl, pentyl and hexyl. Alkyl residues of R2 and R3 may be branched alkyl residues such as tert-butyl. Alkyl residues of R4 and R5 may be straight-chain such as ethyl, propyl, butyl, pentyl, and hexyl. Examples of alkenyl residues are straight-chain alkenyl residues such as vinyl, 1- and 2-propenyl, and 2-butenyl. Ethynyl, 1- and 2-propynyl and 1- and 2-butynyl are examples of alkynyl residues. Examples of C2-8-alkanoyl residues are straight-chain alkanoyl residues such as acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl and octanoyl.
In one embodiment of the invention the pyridine-carboxylic acid residue in the compounds of Formula I is a nicotinic acid residue, that is, when R1 is hydrogen (e.g., a nicotinic acid residue linked in the 5- or 6-position). In one embodiment, R2 and R3 taken together are —(CR6R7)n—. In a further embodiment, R2 and R3 taken together are —C(CH3)2CH2CH2C(CH3)2—, —C(CH3)2(CH3)2—, or —C(CH3)2(CH2)4—. In one embodiment, Y is oxygen. In one embodiment, R4 is C2-8-alkyl. In one embodiment, R1 is hydrogen.
Examples of compounds of Formula I are the following: 




Other examples of compounds of formula I are:

    
    
        6-(3-hexyl-5,5-dimethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl-carbonyloxy)-nicotinic acid,
        6-(3-hex-1-enyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-carbonyloxy)-nicotinic acid,
        6-(6-hexyl-3,3-dimethyl-indan-5-yl-carbonyloxy)-nicotinic acid,
        6-(3-butoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-carbonyloxy)-nicotinic acid,
        6-(3-adamantan-1-yl-4-hydroxy-benzoyloxy)-nicotinic acid,
        6-(3-hexanoyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-carbonyloxy)-nicotinic acid, and
        6-(3-hexyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-carbonylsulphanyl)-nicotinic acid.
    
    


Methods of manufacturing compounds of the present invention are set forth in U.S. Pat. No. 5,726,191.
In one embodiment, the topical carrier substantially dissolves said compound (e.g., dissolves at least 90% of the compound). In one embodiment, the topical carrier suspends the compound. In one embodiment, the composition comprises about 0.001% to about 1%, by weight, of the compound (e.g., about 0.01% to about 0.1%, by weight).
In one embodiment, the method includes admixing a unit dose of the compound (e.g., an amount of the compound sufficient for a single application of the compound). In a further embodiment, the topical carrier comprises an alcohol. Examples of such alcohols include, but are not limited to, the group consisting of ethanol, isopropyl alcohol, and propylene glycol. In one embodiment, the topical carrier further includes an gelling agent. In one-embodiment, the gelling agent is an oil-soluble gelling agent. Suitable gelling agents for oils (such as mineral oil) include, but are not limited to, hydrogenated butylene/ethylene/styrene copolymer and hydrogenated ethylene/propylene/styrene copolymer. Such gels typically comprises between about 0.1% and 5%, by weight, of such gelling agents.
In another embodiment, the method includes admixing multiple unit dosages of the compound. In a further embodiment, the topical carrier comprises a member selected from the group consisting of diisopropyl adipate, diisopropyl sebacate, diisocetyl adipate, triacetin, caprylic/capric triglyceride, and isopropyl myristate. In a further embodiment, the method further includes the step of refrigerating the resulting formulation during the course of administration of the multiple unit dosages.
In one embodiment, the method further comprises admixing the formulation containing the compound with a cream (e.g., a water-in-oil emulsion or oil-in-water emulsion) or a gel (e.g., an aqueous, petrolatum, or silicone gel).
In another aspect, the invention features a kit comprising two chambers, wherein the first chamber contains the compound in solid form and the second chamber contains a topical carrier in an amount capable of dissolving or dispersing said compound where the compound is of Formula I.
In one embodiment, the topical carrier is in an amount capable of substantially dissolving the compound. In one embodiment, the topical carrier is in an amount capable of suspending the compound.
In one embodiment, the first chamber contains a unit dose of the compound. In a further embodiment, the topical carrier contains an alcohol. In a further embodiment, the second chamber further contains a gelling agent.
In one embodiment, the first chamber contains multiple unit dosages of the compound. In a further embodiment, the solvent is selected from the group consisting of diisopropyl adipate, diisopropyl sebacate, diisocetyl adipate, triacetin, caprylic/capric triglyceride, and isopropyl myristate. In a further embodiment, the kit further includes a label instructing the user to refrigerate the compound following dissolution.
In one embodiment, the kit further comprises a third chamber containing a cream (e.g., a water-in-oil emulsion or oil-in-water emulsion) or a gel (e.g., an aqueous, petrolatum, or silicone gel).
In one embodiment, the first chamber and second chamber are separate containers (e.g., vials). The contents of one container may then be added and admixed with the contents of the other container (e.g., the compound may be removed from its container and added and admixed with the topical carrier in its container). In a further embodiment, the resulting mixture is administered by using a wipe applicator that may or may not be stored within the other container. Examples of such administration is well known in the art, e.g., Benzamycin® topical gel.
In another embodiment, the two chambers are within the same container, but are separated by a wall that is breakable upon the application of force. Examples of two chamber packages for delivery of unit dosages are well known in the art and are available from supplier such as Klocke Verpackungs GmbH (Weingarten, Germany). In a further embodiment, the resulting mixture is administered by using a wipe applicator that may or may not be stored within the container.
Unit dosages may also be administered using applicator stick wherein the topical carrier is stored within the shaft of the applicator and separated from the applicator end of stick by a breakable wall. The compound of Formula 1 is contained within the applicator end of the stick (e.g., a foam or fabric tip). Upon rupturing the breakable wall, the topical carrier enters the foam head and dissolves/suspends the compound. Examples of such applicators are well known in the art, e.g., Betadine PrepStickTM applicator (Purdue Frederick, Norwalk, Conn.).
The compounds of the present invention are useful in the treatment or prevention of skin disorders such as acne, psoriasis, photo-damage, environmental damage, intrinsic age damage, wrinkles, tumors (e.g., melanomas), hyperpigmentation, and skin roughness. The compounds of the present invention may also be used for the promotion of wound healing. Other uses of the present invention are set forth in U.S. Pat. No. 5,726,191.
As discussed above, compounds of the present invention were found to be chemically unstable once formulated into a topical carrier. What is meant by a topical carrier is a liquid or semi-solid formulation capable of being applied topically to the skin. Examples of topical carriers include, but are not limited to, ointments, sprays, creams, lotions (e. g., solutions, suspensions and emulsions), or gels. The topical carrier is preferably anhydrous.
Thus, in order to ensure stability of such compounds, they must be stored in solid form, and then reformulated into a topical carrier proximate to the time of first application (e.g., within seven days prior to the first topical administration of said compound). In one embodiment, the compound is reformulated within forty-eight (48) hours prior to first topical administration of said compound. In one embodiment, the compound is mixed by a doctor, pharmacist, or by the end user.
The following is a description of the manufacture of various topical formulations of the present invention. Other formulations of the invention can be prepared in an analogous manner by a person of ordinary skill in the art.


EXAMPLE 1
The stability of Compound I was tested in the following twenty-eight different topical formulations, set forth in Table 1. Finsolv® TN is a C12-15 alkyl benzoate from Fintex, Inc. (Elmwood Park, N.J.) Miglyol® 812 from Huls AG (Marl, Germany) and Neobee® 1053 from Stepan Company (Northfield, Ill.) are each a caprylic/capric triglyceride.











TABLE 1







Formulation No.
Carrier
Volume %




















Formulation 1
Diisopropyl sebacate
100



Formulation 2
Diisopropyl sebacate
60




Cyclomethicone
40



Formulation 3
Miglyol ® 812
100



Formulation 4
Isopropyl laurate
100



Formulation 5
Diisopropyl sebacate
50




Isopropyl laurate
50



Formulation 6
Diisopropyl adipate
50




Cyclomethicone
50



Formulation 7
Diisopropyl adipate
100



Formulation 8
Diisopropyl adipate
50




Isopropyl laurate
50



Formulation 9
Propylene glycol
100



Formulation 10
PEG 400
100



Formulation 11
Propylene carbonate
100



Formulation 12
Dimethyl isosorbide
100



Formulation 13
Miglyol ® 812
100



Formulation 14
Finsolv ® TN
100



Formulation 15
Glycerin
100



Formulation 16
Isopropyl myristate
100



Formulation 17
Cyclomethicone
100



Formulation 18
Dimethicone
100



Formulation 19
Mineral oil
100



Formulation 20
Sunflower oil
100



Formulation 21
Soybean oil
100



Formulation 22
Neobee ® 1053
100



Formulation 23
Sesame oil
100



Formulation 24
Butyl Acetate
100



Formulation 25
Isopropanol
100



Formulation 26
PEG 400
30




Ethanol
70



Formulation 27
Triacetin
100



Formulation 28
Tributyrin
100










The general procedure to prepare the above formulations is as follows. A 500 mg of Compound 1 was weighed and transferred into an 800 ml glass beaker containing 500 g of one of the above carriers. The formulation was then stirred with a paddle mixer (stirrer type RZR50 from Caframo in Wiarton, Ontario, Canada) at 100 RPM setting until the compound was completely dissolved/dispersed in the carrier.
About 20 g each of the resulting formulations were then packed into 24 clear glass scintillation vials of 20 ml volume (Wheaton Disposable Scintillation Vials from Wheaton Scientific in Milleville, N.J.) and labeled. Groups of eight of such vials were then stored at 4° C., RT (22° C.) and/or 40° C. for stability studies.
The samples of the formulations at each of the above three temperatures were then periodically analyzed for the chemical stability of Compound 1. The compound was assayed using high performance liquid chromatographic (HPLC) system. The results of this analysis is set forth in Table 2 setting forth the amount of Compound 1 remaining in the formulation following a certain number of days at specified temperatures. Chemical degradation of Compound 1 was seen in all of the formulations stored at 22° C. and/or 40° C., thus, demonstrating a need to make the formulation proximate to the time of administration and/or refrigerate the formulation after it is made.









TABLE 2









% Remaining











Formulation No.
Days
4° C.
22° C.
40° C.














Formulation 1
84
102
89
64


Formulation 2
84
101
90
68


Formulation 3
56
100
93
60


Formulation 4
56
100
97
87


Formulation 5
56
100
96
80


Formulation 6
90
87
84
63


Formulation 7
90
87
80
57


Formulation 8
90
100
93
69


Formulation 9
36
82.39
—
0.71


Formulation 10
36
93.56
—
0.71


Formulation 11
70
100.77
—
40.18


Formulation 12
18
96.84
—
65.36


Formulation 13
70
93.46
—
49.09


Formulation 14
36
100.48
—
2.23


Formulation 15
29
97.44
—
84.09


Formulation 16
22
95.43
—
86.18


Formulation 17
85
100
—
83


Formulation 18
30
98.16
—
76.18


Formulation 19
70
104.83
—
84.83


Formulation 20
70
102.20
—
51.83


Formulation 21
22
101.34
—
83.82


Formulation 22
21
100
97.38
88.62


Formulation 23
23
102.66
—
86.77


Formulation 24
34
100
—
55.48


Formulation 25
18
100
80.79
5.96


Formulation 26
13
100
86.74
9.13


Formulation 27
23
100
96.41
93.81


Formulation 28
22
100
97.49
86.08









It is understood that while the invention has been described in conjunction with the detailed description thereof, that the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the claims.

## Claims

1. A method of enhancing the stability during administeration of multiple unit dosages of a compound of Formula I: 



wherein 
R1 is hydrogen or C1-6-alkyl; 
R2 is C1-6-alkyl or adamantyl; 
R3 is C1-6-alkyl or hydroxy; or 
R2 and R3 taken together are —(CR6 R7)n—; 
R4 is C2-8-alkyl, C2-8-alkenyl, C2-8-alkynyl, —OCH2R5 or C2-8-alkanoyl, or hydrogen when R3 is hydroxy; 
R5 is C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl; 
R6 and R7 are hydrogen or C1-6-alkyl; 
Y is oxygen or sulfur; and 
n is 3, 4, or 5, 
or a pharmaceutically acceptable salts of carboxylic acid of formula I, 
wherein said method comprises the step of admixing multiple unit dosages of said compound in solid form with a topical carrier to form a topical formulation within forty-eight hours prior to first topical administration of said formulation, and refrigerating said formulation during the course of administration of said multiple unit dosages.

2. A method of claim 1, wherein said topical carrier substantially dissolves said compound.

3. A method of claim 1, wherein said topical carrier suspends said compound.

4. A method of claim 1, wherein said topical carrier further comprises a gelling agent.

5. A method of claim 2, wherein said topical carrier comprises a member selected from the group consisting of diisopropyl adipate, diisopropyl sebacate, diisocetyl adipate, triacetin, caprylic/capric triglyceride, and isopropyl myristate.

6. A method of claim 1, wherein said formulation comprises about 0.01% to about 0.1%, by weight, of said compound.

7. A method of claim 5, wherein said method further comprises admixing said formulation comprising said compound with a cream or a gel.

8. A method of claim 1, wherein said method further comprises admixing said formulation comprising said compound with a cream or a gel.

9. A method of claim 1, wherein said compound is 




or a pharmaceutically acceptable salt thereof.

10. A method of claim 2, wherein said compound is 




or a pharmaceutically acceptable salt thereof.

11. A method of claim 3, wherein said compound is 




or a pharmaceutically acceptable salt thereof.

12. A method of claim 4, wherein said compound is 




or a pharmaceutically acceptable salt thereof.

13. A method of claim 5, wherein said compound is 




or a pharmaceutically acceptable salt thereof.

14. A method of claim 6, wherein said compound is 




or a pharmaceutically acceptable salt thereof.

15. A method of claim 7, wherein said compound is 




or a pharmaceutically acceptable salt thereof.

16. A method of claim 8, wherein said compound is 




or a pharmaceutically acceptable salt thereof.

17. A method of claim 1, wherein said topical carrier comprises a member selected from the group consisting of diisopropyl adipate, diisopropyl sebacate, diisocetyl adipate, triacetin, caprylic/capric triglyceride, and isopropyl myristate.

18. A method of claim 17, wherein said formulation comprises about 0.01% to about 0.1%, by weight, of said compound.

19. A method of claim 17, wherein said compound is 




or a pharmaceutically acceptable salt thereof.

20. A method of claim 18, wherein said compound is 




or a pharmaceutically acceptable salt thereof.