111111
`
`1111111111111111111111111111111111111111111111111111111111111111111111111111
`US 20060204526Al
`
`(19) United States
`c12) Patent Application Publication
`Lathrop et al.
`
`(10) Pub. No.: US 2006/0204526 Al
`Sep. 14, 2006
`(43) Pub. Date:
`
`(54) EMULSIVE COMPOSITION CONTAINING
`DAPSONE
`
`(76)
`
`Inventors: Robert William Lathrop, Fort Collins,
`CO (US); David W. Osborne, Santa
`Rosa, CA (US)
`
`(30)
`
`Foreign Application Priority Data
`
`Feb. 24, 2005
`Aug. 13, 2004
`
`(WO) .................................... 2005/016296
`(WO) ........................... PCT/US04/26351
`
`Publication Classification
`
`Correspondence Address:
`Schwegman, Lundberg, Woessner & Kluth, P.A.
`P.O. Box 2938
`Minneapolis, MN 55402 (US)
`
`(51)
`
`Int. Cl.
`(2006.01)
`A61K 9100
`(2006.01)
`A61K 311135
`(52) U.S. Cl. ............................................ 424/400; 514/646
`
`(21) Appl. No.:
`
`111352,935
`
`(22) Filed:
`
`Feb. 13, 2006
`
`Related U.S. Application Data
`
`(63) Continuation of application No. PCT/US04/26447,
`filed on Aug. 13, 2004.
`
`(60) Provisional application No. 60/494,912, filed on Aug.
`13, 2003.
`
`(57)
`
`ABSTRACT
`
`The present invention relates to a topical, emulsive compo(cid:173)
`sition containing Dapsone or its derivative. The inventive
`composition incorporates emollients and Dapsone or its
`derivative in a stable emulsion. The stability is achieved
`through the use of a combination of certain surfactant
`mixtures and an enhancer providing solubility of the Dap(cid:173)
`sone.
`
`1
`
`AMN1006
`
`

`

`US 2006/0204526 AI
`
`Sep. 14,2006
`
`1
`
`EMULSIVE COMPOSITION CONTAINING
`DAPSONE
`
`STATEMENT OF PRIORITY
`
`[0001] This application is a Continuation Under 35 U.S.C.
`§ l.lll(a) of International Application No. PCTIUS2004/
`026447, filed Aug. 13, 2004 and published in English as WO
`2005/016296 on Feb. 24, 2005, which claims the benefit
`under 35 U.S.C. § 119(e) of U.S. Provisional Application
`No. 60/494,912 filed Aug. 13, 2003, which applications are
`incorporated herein by reference.
`
`BACKROUND OF THE INVENTION
`
`[0002] DDS or 4,4'-diaminodiphenyl sulfone has the USP
`name, Dapsone, and is a well-known medicament possess(cid:173)
`ing several beneficial medicinal activities. Dapsone is typi(cid:173)
`cally administered as one of the medicinal agents used in the
`treatment of leprosy. Dapsone and its derivatives are also
`effective for treatment of bacterial infections, protozoanal
`infections such as malaria, pneumocystis carinii, and plas(cid:173)
`monic infections such as toxoplasmosis. Some of the early
`publications describing Dapsone and its derivatives include
`a 1938 French patent (FR829,926) and U.S. Pat. No. 2,385,
`899. These references explain that Dapsone has an inhibiting
`effect on the growth of bacteria, mycobacteria, an plasmo(cid:173)
`dia. According to the 2001 Physicians Desk Reference,
`Dapsone is commercially available in tablet form from
`Jacobus Pharmaceutical Company. Dapsone also used as a
`cross-linking agent for epoxy resins.
`
`[0003] Dapsone is also known to be useful as an anti(cid:173)
`inflammatory agent. It has been used to treat skin diseases
`characterized by the abnormal infiltration of neutrophils,
`such as Dermatitis herpetiformis, linear IgA dermatosis,
`pustular psoriasis, pyoderma gangrenosum, acne vulgaris,
`and Sweet's Syndrome.
`
`[0004]
`In all of these applications including topical appli(cid:173)
`cations, Dapsone treatment is systemic and the drug is
`administered orally. No topical formulation of Dapsone is
`commercially available for local treatment of skin disease
`and references describing topical administration of Dapsone
`are not common. Of the few scientists considering topical
`administration, Osborne (U.S. Pat. Nos. 5,863,560 and
`6,060,085) is one providing a topical formulation of Dap(cid:173)
`sone. He describes a dermatological gel composition con(cid:173)
`taining Dapsone.
`
`[0005] One reason for the lack of commercial topical
`formulations rests upon the solubility character of Dapsone
`and its derivatives. Dapsone and many of its derivatives are
`soluble in ethanol, methanol, acetone and dilute, aqueous
`HCl but are practically insoluble in water and in oils such as
`petroleum gel, wax and vegetable oils. Consequently, topical
`formulations of Dapsone in water or oils are difficult to
`develop. Those topical formulations of Dapsone that have
`been developed typically include salt formers and solubi(cid:173)
`lizing agents that enable formation of a single phase aqueous
`solution or gel. The solubilizing agents are water miscible
`and include such organic liquids as ethylene diglycol mono(cid:173)
`ethyl ether and ethanol.
`
`oils and natural skin softeners from the skin thus causing it
`to be dry, itch and crack. Inclusion of exogeneous skin
`emollients, oils and the like, however, causes phase separa(cid:173)
`tion and precipitation of Dapsone. Use of typical emulsifiers
`does not solve the Dapsone precipitation owing to the
`lowered Dapsone solubility and conflicting physical char(cid:173)
`acteristics of the phases of the resulting composition.
`
`[0007] Therefore, there is a need to formulate a stable,
`aqueous based, emulsive Dapsone composition that will not
`dry or crack the skin. There is a further need to formulate
`such a composition with pharmaceutically acceptable ingre(cid:173)
`dients. There is also a need to include exogeneous oils,
`emollients and the like in such an emulsion without causing
`separation or precipitation of the Dapsone.
`
`SUMMARY OF THE INVENTION
`
`[0008] These and other needs are achieved by the present
`invention which provides a stable, emulsive composition
`containing Dapsone or a derivative thereof. The emulsive
`composition enables the use of a wide variety of oil phase
`components as vehicles for the topical (skin or mucosa)
`delivery of Dapsone or a derivative thereof. The emulsive
`composition of the invention also provides for the use of
`polar phase components for the augmented delivery and
`enhancement of Dapsone or a derivative thereof on the skin
`or mucosa.
`
`[0009] Accordingly, the present invention is directed to an
`emulsive composition of the following components: a) Dap(cid:173)
`sone or its derivative (hereinafter collectively termed Dap(cid:173)
`sone), b) a solvation medium (polar phase component) for
`Dapsone c) an emulsifier system, d) an oil phase component,
`e) optional water and f) optional gelation or thickening
`agents. Excipients as well as other additives and colorants
`may also be included as additional compounds in the sol(cid:173)
`vation medium (polar phase) and oil phase components.
`Each of the components of the emulsive composition
`(except the optional water) can be composed of one or more
`individual compounds falling within the component descrip(cid:173)
`tion.
`
`[0010] The solvation medium (polar phase) may be an
`organic solvent that ranges in water solubility from moder(cid:173)
`ately soluble (for example having from 2% to 10% by
`weight solubility in water) to completely miscible in water
`in all proportions. The solvation medium will at least
`partially, and preferably will completely dissolve Dapsone.
`When optional water is combined with the solvation
`medium, the combination also at least partially, and prefer(cid:173)
`ably completely, dissolves the Dapsone. In either aspect, the
`solvation medium or solvation medium plus water dissolves
`or disperses the Dapsone as a stable solution or dispersion.
`When the combination of solvation medium and water are
`employed, that combination is the polar phase (an aqueous
`polar phase) and the solvation medium preferably enhances
`the solubility of the Dapsone in this aqueous polar phase.
`Preferred organic solvents that function as the solvation
`medium either alone or in combination with water include a
`polyglycol, a polyol, a polyglycol ether, a polyol ether, a
`polyglycol monoether or a polyol monoether or a combina(cid:173)
`tion thereof.
`
`[0006] However, use of such topical formulations of Dap(cid:173)
`sone is also problematic. These topical formulations typi(cid:173)
`cally act as drying agents for the skin. They remove essential
`
`[0011] The oil phase component includes any pharmaceu(cid:173)
`tically acceptable organic, hydrophobic substance that soft(cid:173)
`ens and moistens the skin layers such as the epidermis and
`
`2
`
`

`

`US 2006/0204526 AI
`
`Sep. 14,2006
`
`2
`
`dermis. Waxes, oils, fatty acids, polyols, and esterified fatty
`acids are some examples of the oil phase component.
`
`[0012] The emulsifier system has both ionic and nonionic
`properties so that it stabilizes the emulsive composition of
`the invention and prevents Dapsone separation. Preferably,
`the ionic properties are anionic properties. The combination
`of these properties can be achieved by a mixture of surfac(cid:173)
`tant and a saturated and/or unsaturated fatty alcohol. In
`particular, a blend of a CIO to C24 saturated and/or unsat(cid:173)
`urated fatty alcohol, and any one of more of a CS to C24
`saturated and/or unsaturated fatty alcohol phosphate ester or
`diester, a CS to C24 saturated and/or unsaturated fatty
`alcohol sulfate ester or diester, a CS to C24 saturated and/or
`unsaturated fatty alcohol carbonate ester or diester as well as
`derivatives of such saturated and/or unsaturated fatty alcohol
`phosphate, sulfate and/or carbonate esters may serve as the
`emulsifier system according to the invention. Preferably, the
`emulsifier system is a combination of a Cl2 to CIS fatty
`alcohol, a phosphate diester of a Cl2 to CIS fatty alcohol
`and a phosphate monoester of an unsaturated Cl2 to CIS
`fatty alcohol.
`
`[0013] According to the invention, the concentrations of
`the components by weight relative to the total weight of the
`emulsive composition are as follows:
`
`[0014] a) Dapsone may range from about 0.005 percent
`to about 30 percent, preferably about 0.1 percent to
`about 25 percent, more preferably about 0.1 percent to
`about 15 percent, especially more preferably about 0.1
`percent to about I 0 percent, very especially more
`preferably about 0.2 percent to about S percent, and
`most preferably about 0.5 to about 5 percent by weight
`of the emulsive composition, with such percentages as
`I, 2, 5 and 7.5 being especially preferred embodiments
`thereof;
`
`[0015] b) The solvation medium may range from about
`0.5 percent to about 99 percent, preferably about 0.5
`percent to about 50 percent, more preferably about 5
`percent to about 40 percent, especially more preferably
`about 5 percent to about 35 percent, most preferably
`about 5 percent to about 30 percent;
`
`[0016] c) The emulsifier system may range from about
`0.1 percent to about 30 percent, preferably about 0.5
`percent to about 25 percent, more preferably about I
`percent to about 25 percent, most preferably about 5
`percent to about 25 percent, most preferably about 5
`percent to about 20 percent;
`
`[0017] d) The oil phase may range from about 0.1
`weight percent to about 75 percent, preferably about
`0.1 to about 50 percent, more preferably about I to
`about 45 percent, most preferably about 2 to about 40
`percent;
`[0018] e) Water may range from 0 percent to about 99
`percent, preferably from 0 to about 50 percent, more
`preferably from 0 to about 40 percent, most preferably
`from 0 to about 35 percent, i.e., water is optional;
`f) The amounts are combined to equal 100
`[0019]
`percent, and except for water, each of the components
`a-d is to be included. Each of the four ingredient
`components a-d may be composed of one or more
`individual compounds falling within the designated
`component category.
`
`[0020] The emulsive composition of the invention pro(cid:173)
`vides therapeutic benefits such as, but not limited to, anti(cid:173)
`inflammatory activity, antibacterial activity, anti-itch activ(cid:173)
`ity and emollient properties so that it is useful in the
`treatment of such dermatological disorders as psoriasis,
`dermatitis and the itch associated with healing or gealed
`burn wounds while maintaining skin and/or mucosal integ(cid:173)
`rity, flexibility, stretch and moisturization.
`
`Definitions
`[0021] As used herein, certain terms have the following
`meanings. All other terms and phrases used in this specifi(cid:173)
`cation have their ordinary meanings as one of skill would
`understand. Such ordinary meanings may be obtained by
`reference to such technical dictionaries as Hawley's Con(cid:173)
`densed Chemical Dictionary II th Edition, by Sax and Lewis,
`Van Nostrand Reinhold, New York, N.Y., 19S7; The Merck
`Index, 11th Edition, Merck & Co., Rahway N.J. 19S9; The
`Physician's Desk Reference (PDR), 2001 Edition, Medical
`Economics Company, Montvale, N.J.; Stedman's Medical
`Dictionary, 25'h Edition, Williams & Wilkens, Baltimore,
`Md., 1990.
`
`[0022] Dapsone is 4,4'-diaminodiphenyl sulfone. It has the
`chemical formula C 12H 12N20 2 S and is alternatively known
`as 4,4'-sulfonyldianiline or bis ( 4-aminophenyl)sulfone (also
`spelled sulphone). See the above-referenced Merck Index at
`entry no. 2S20.
`
`[0023] Derivatives of Dapsone refer to compounds that
`have a similar chemical structure and thus similar therapeu(cid:173)
`tic potential to Dapsone. These include compounds with two
`organic substituents (Ru R2 ) at the two amino groups
`(R,R2NC 6H4 S02C 6 H4 NR1R2 ). R 1 and/or R2 each may be
`hydrogen, cl to c6 alkyl, cl to c6 alkoxyoyl as well as a
`substituted alkyl group of I to 6 carbons wherein the
`substituent may be hydroxyl, thio, alkoxy, halo, amido and
`similar polar or lipophilic substituents. Preferably, R 1 and R2
`are the same. When the R 1 and R2 substitution is R=CHO,
`the compound formed is generically named diformy!Dap(cid:173)
`sone. It is alternatively known as bis (4-formaminophenyl(cid:173)
`)sulfone and 4,4'-diformyldiaminodiphenyl sulfone. When
`the R 1 and R2 substitution is R COCH3, the compound
`formed is AceDapsone, alternatively named bis (4-acetami(cid:173)
`dophenyl)sulfone and 4,4'-diacetyldiaminodiphenyl sulfone.
`AceDapsone is a known prodrug of Dapsone. Other deriva(cid:173)
`tives known to have antibacterial and/or anti-inflammatory
`effect are glucosulfone sodium, solapsone, diathymosulfone,
`acediasulfone, monoacetyl Dapsone, acetosulfone, succisul(cid:173)
`fone, aldesulfone sodium, and thiazolsulfone. Additional
`Dapsone derivatives are described in the following journal
`articles, the disclosures of which are incorporated herein by
`reference: M.D. Colman eta!. J. Pharm. Pharmacal., 1997,
`49, 53-57; J. Pharm. Phamracol., 1996, 4S, 945-50; Envi(cid:173)
`ronmental Toxicology and Pharmacology, 1996, 2, 3S9-395.
`
`[0024] An emulsifYing agent is a surfactant (defined sepa(cid:173)
`rately below). However, not all surfactants are emulsifying
`agents. An emulsifYing agent is typically a term used to
`describe an organic compound that stabilizes a uniform
`dispersion of one solvent in another where the two solvents
`are immiscible. Portions of the emulsifYing agent dissolve in
`the different phases so that the dispersion is prevented from
`coalescing into two separate liquids.
`
`[0025] A fatty alcohol is a saturated or unsaturated CS to
`C40 alcohol that may or may not be substituted by additional
`
`3
`
`

`

`US 2006/0204526 AI
`
`Sep. 14,2006
`
`3
`
`groups such as halo, alkoxy of 1 to 6 carbons, alkyl keto of
`2 to 6 carbons, alkoxycarbonyl of 2 to 6 carbons, alkyl
`amido of 2 to 6 carbons and alkye amine of 1 to 6 carbons
`optionally substituted with 1 or 2 alkyl groups of 1 to 4
`carbons on the amine.
`
`[0026] The terms "insoluble" and "immiscible", as applied
`to two liquids, mean that one liquid displays essentially no
`solubility in the second. While the measurable solubility
`need not be zero, for the practical purposes of formulating
`topical products, the level of solubility is insignificant if an
`ingredient is described as insoluble or immiscible in another.
`
`[0027] The term "miscible" when used in connection with
`two liquids means that the two liquids are soluble in each
`other at all ratios.
`
`[0028] A solution is a system at chemical equilibrium in
`which a solute (liquid, solid, or gas) is dissolved in a liquid
`solvent.
`
`[0029] A surfactant or surface active agent is an organic
`compound that reduces the surface tension when dissolved
`in water or water solutions. In an emulsion, a surfactant will
`contain a hydrophilic portion and a lipophilic portion by
`which it functions to reduce the surface tension of the
`surfaces between immiscible phases. Functionally, in der(cid:173)
`matological applications, surfactants include emulsifying
`agents, wetting agents, cleansing agents, foam boosters, and
`solubilizing agents. A surfactant is any nonionic, anionic, or
`cationic organic compound of moderate to high molecular
`weight (such as from about 100 to 300,000 daltons) for
`which a significant portion of the molecule is hydrophilic
`and a significant portion is lipophilic.
`
`[0030] The term "pharmaceutically active agent" is used
`to refer to a chemical material or compound that is suitable
`for topical administration and induces a desired physiologi(cid:173)
`cal effect.
`
`[0031] The term "topical administration" means the deliv(cid:173)
`ery of a composition or active agent to the skin or to mucosal
`tissue. A topical composition is one that is suitable for
`topical administration.
`
`[0032] The term "about" means a variation of 10 percent
`of the value specified; for example about 50 percent carries
`a variation from 45 to 55 percent.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`[0033] The present invention solves the formulation and
`treatment problems associated with topical administration of
`Dapsone and its derivatives (hereinafter collectively termed
`Dapsone). These compounds are aromatic, are substituted
`with diamino groups and are difficult to formulate as aque(cid:173)
`ous based topical compositions. The compounds themselves
`readily separate and/or precipitate from such aqueous based
`compositions. When solvation enhancers are used, the
`resulting compositions typically cannot include desirable,
`oil-based skin conditioning agents. Such skin conditioning
`agents, however, are common formulation ingredients for
`topical compositions because without them, topical compo(cid:173)
`sitions often dry, redden and are detrimental to the skin.
`
`[0034] According to the invention, it has been discovered
`that combinations of solvation medium ingredients and
`emulsifiers enable the formulation of Dapsone topical com-
`
`positions that include oil-based skin conditioning agents. In
`particular, the emulsive composition of the invention
`includes Dapsone, a solvation medium, an emulsifier system
`and one or more oil-based skin conditioning agents. An
`alternative emulsive composition of the invention includes
`water with the solvation medium so as to provide an aqueous
`polar phase.
`
`[0035] The emulsive composition of the present invention
`may display a consistency and feel characteristic of products
`suitable to application to the skin or a mucous membrane.
`The consistency of the composition may be a freely-flowing
`liquid. Such a consistency allows for a rapid spreading on
`the skin and an ease of application. Alternately, the consis(cid:173)
`tency of the composition may range to a stiff or firm,
`semi-solid. A stiff consistency may be suitable for a heavier
`application of the composition to a limited site on the skin
`or on a mucous membrane. Further, a stiff consistency
`resulting from a high oil phase may contribute to the
`occlusive property of the composition on the skin or a
`mucous membrane. The feel of the composition on the skin
`may range from a thin, wet feel to a stiff, waxy feel. With the
`adjustment of the various ingredients the composition can be
`formulated to display a consistency and feel optimal for the
`delivery of the Dapsone for an intended indication.
`
`Composition of the Invention
`[0036] Many dermatological products are described as
`emulsions but the two immiscible phases forming such
`products often do not form colloidal mixtures. Instead, the
`internal phases are dispersed as droplets within the continu(cid:173)
`ous phases to create temporarily stable systems. The chemi(cid:173)
`cal equilibria in such systems are toward the separation of
`the immiscible phases.
`
`[0037] A system may be said to be at chemical equilibrium
`when it is stable theoretically forever as a result of random
`molecular movement. In contrast, a physically stable topical
`emulsion system often involves a practical and limited
`stability. An emulsion may be classified as physically stable
`when it displays no or insignificant change in the phase
`dispersion over a defined period of time. For a dermatologi(cid:173)
`cal emulsion product, a physically stable system typically is
`a system that shows no or insignificant change in the phase
`dispersion over the period of a marketable self-life.
`
`[0038]
`In dermatological or topical products, common
`emulsions are oil-in-water emulsions and water-in-oil emul(cid:173)
`sions. In the former, the oil phase is the internal phase
`dispersed in the continuous water phase. In the latter, the oil
`phase may be the continuous phase. More complex emulsion
`systems have been described and formulated as dermato(cid:173)
`logical products. Water-in-oil-in-water emulsions and other
`complex combinations may be formed between immiscible
`phases.
`
`In many topical emulsions, an internal oil phase
`[0039]
`contains oily or fatty excipients that are solid at room
`temperature, thereby raising a point of confusion over the
`definition of an emulsion as a liquid-in-liquid dispersion.
`This point is clarified by the understanding that at the time
`of formation, the emulsion is a liquid-in-liquid dispersion
`because the oil phase may have been heated or otherwise
`manipulated by make it a liquid. It may also be noted that at
`the water/oil interface the precise nature of the physical state
`of the oil phase as either a liquid or a solid is not a simple
`characterization.
`
`4
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`US 2006/0204526 AI
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`Sep. 14,2006
`
`4
`
`[0040] The oil phase of a topical emulsion may contain
`oily or fatty materials that are miscible or compatible with
`each other but that have no or insignificant miscibility or
`solubility in water. As many oil phase excipients are solids
`at standard temperature, the miscibility is commonly evalu(cid:173)
`ated with the excipients in their liquid states.
`
`In topical or dermatological products, the water
`[0041]
`phase, or aqueous phase, often contains an amount of water
`and optionally a variety of liquids or solids that are soluble,
`miscible, or dispersed in the water.
`
`[0042] Many of these properties are present in the emul(cid:173)
`sive composition of the present invention. However, water
`need not be present in combination with the solvation
`medium according to the invention.
`
`In the following discussion, use of the term "Dap(cid:173)
`[0043]
`sone" shall mean Dapsone or its derivative unless otherwise
`stated.
`
`[0044] The present invention provides a physically stable
`emulsive composition containing Dapsone in a solvation
`medium (polar phase) in combination with at least one oil
`phase component (oil phase) and an emulsifying system.
`The solvation medium (polar phase) includes an organic
`solvent for solvating the Dapsone. Optionally, the solvation
`medium may contain additional compounds such as com(cid:173)
`mon excipients, coloring agents and the like. Also option(cid:173)
`ally, the solvation medium may form a combination with
`water to act as the polar phase.
`
`[0045] The emulsifying system may be a combination of
`a fatty alcohol and a surfactant.
`
`[0046] The emulsive composition can be formulated into
`a range of topical compositions, from light, non-greasy
`lotions to heavy, emollient creams.
`
`[0047] According to the invention, the concentration of
`Dapsone may be any amount that provides effective anti(cid:173)
`bacterial and/or anti-inflammatory properties to the emul(cid:173)
`sive composition. In particular, the concentration of Dap(cid:173)
`sone in the emulsive composition of the invention may range
`from about 0.05 percent to about 30 percent by weight of the
`emulsion formulation. Preferably, this concentration may be
`from about 0.1 percent to about 25 percent, more preferably
`about 0.1 percent to about 15 percent, especially more
`preferably about 0.1 percent to about 10 percent, very
`especially more preferably about 0.2 percent to about 8
`percent, and most preferably about 0.5 to about 5 percent by
`weight of the emulsive composition. The Dapsone concen(cid:173)
`tration of especially preferred embodiments may be such
`percentages as 1, 2, 5 and 7.5.
`
`[0048] According to the invention, the solvation medium
`may be an organic solvent that is moderately soluble to
`miscible with water and dissolves Dapsone or enables
`dissolution of Dapsone in the combination of solvation
`medium and optional water. The solvation medium or its
`combination with water acts as the polar phase of the
`emulsive composition.
`
`[0049] Preferably, in either alternative, namely, use of an
`organic solvent or solvents alone as the solvation medium or
`use of the combination of the organic solvent or solvents and
`the water enables the complete dissolution of Dapsone in the
`emulsive composition. However, the amount of the organic
`solvent used alone as the solvation medium or the concen-
`
`tration of organic solvent in the combination of water and
`solvation medium may also enable partial dissolution of the
`Dapsone in the emulsive composition. In the latter situation,
`the portion of Dapsone not dissolved in the solvation
`medium or combination may be suspended as a dispersion of
`microparticles or micronized particles and the like in the
`emulsive composition. Alternatively, the portion of Dapsone
`not dissolved may be suspended as a dispersion of crystal(cid:173)
`line Dapsone. The size of the suspended particles of Dap(cid:173)
`sone may be controlled by the preparation of the Dapsone
`raw material or by the process by which the emulsive
`composition is compounded. The size of the suspended
`particles may range from below 10 microns (microparticles
`or micronized particles) to palpable particles above about
`100 microns. The emulsifYing system participates in the
`maintenance of this dispersion. Alternatively, the undis(cid:173)
`solved portion of Dapsone may be dissolved in the oil phase
`of the emulsive composition when it is formed by combi(cid:173)
`nation of the solvation medium, the oil phase and the
`emulsifYing system.
`
`[0050] Partial dissolution of Dapsone may be the result of
`any one or more of a number of formulation designs. First,
`the organic solvent may not enable complete dissolution of
`the desired concentration of Dapsone in the solvation
`medium even though lower amounts of Dapsone will be
`completely dissolved. Second, the volume of the oil phase
`may be insufficient to dissolve this portion of Dapsone not
`dissolved in the solvation medium. Third, the formation of
`the emulsive composition may decrease the solubility of
`Dapsone in the solvation medium because of interaction of
`the oil phase, the emulsifYing system and the solvation
`medium.
`
`[0051] Notwithstanding the dissolution characteristics of
`Dapsone in the salvation medium and in the emulsive
`composition, in a preferred embodiment of the invention, the
`amounts of Dapsone and organic solvent are selected to fully
`dissolve Dapsone in the neet organic solvent. Although the
`dissolution of Dapsone in organic solvent may be complete,
`subsequent formation of the emulsive composition may
`result in partial precipitation of Dapsone or maintain com(cid:173)
`plete dissolution of Dapsone. Both possibilities are within
`the invention.
`
`[0052] According to the invention, the concentration of
`the solvation medium as the organic solvent alone relative to
`the total weight of the emulsive composition ranges from
`about 0.5 percent to about 99 percent by weight. More
`preferably the concentration of solvation medium is from
`about 0.5 percent to about 50 percent by weight. Especially
`more preferably the concentration of solvation medium is
`from about 5 percent to about 40 percent, very especially
`more preferably about 5 percent to about 35 percent by
`weight, and most preferably about 5 percent to about 30
`percent by weight of the emulsion composition.
`
`[0053] When water is combined with an organic solvent or
`solvents as the solvation medium, the concentration of
`solvation medium relative to the weight of the water plus
`solvation medium ranges from 0.005 weight percent to 98
`weight percent. The ingredients in this instance are the
`organic solvent or solvents and water.
`
`[0054] The concentration of the organic solvent in the
`emulsion will vary depending on the desired Dapsone con(cid:173)
`centration, the solubility of Dapsone in the solvation
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`US 2006/0204526 AI
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`Sep. 14,2006
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`5
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`medium, and the desired extent to which the Dapsone is
`dissolved in the emulsive composition. Dapsone solubility
`in some organic solvents exceeds thirty percent by weight of
`the solution. Its solubility in other organic solvents can be
`less than one percent by weight. Suitable emulsive compo(cid:173)
`sitions can be formulated with an organic solvent calculated
`to dissolve an effective amount of the Dapsone. Further, the
`concentration and ratio of two or more organic solvents may
`be selected for optimal effect depending upon a synergistic
`solubility of Dapsone.
`
`[0055] Organic solvents that are suitable for use as the
`solvation medium in the present invention and are moder(cid:173)
`ately soluble to miscible with water, can be classified into a
`number of broad groups. One group is glycol ethers. A
`glycol ether is an ether formed from at least one glycol and
`at least one lower alkyl alcohol. Preferably the glycol is
`selected from an alkylene glycol such as ethylene glycol,
`propylene glycol, or butylene glycol. The ether portion of
`the glycol ether is a radical of a lower alkyl alcohol such as
`a C1 to C6 alcohol. Preferably, the ether portion alcohol is
`selected from methyl alcohol, ethyl alcohol, propyl alcohol,
`isopropyl alcohol, butyl alcohol, or isobutyl alcohol. The
`glycol ethers have a generalized formula of CxHyOz where
`xis from 4 to 10, y is from about 10 to 22, and z is from 2
`to 5. According to the present invention, the glycol ethers are
`soluble or miscible with water and range in molecular
`formula from C4 to about C10 .
`[0056] Examples of glycol ethers under the classification
`of ethylene glycol ethers include ethylene glycol monopro(cid:173)
`pyl ether (propoxyethanol), ethylene glycol mono butyl ether
`(butoxyethanol), diethylene glycol monomethyl ether
`(methoxydiglycol), diethylene glycol monoethyl ether
`(ethoxydiglycol), diethylene glycol monobutyl ether
`(butoxydiglycol), diethylene glycol monoisopropyl ether
`(isopropyldiglycol), and diethylene glycol monoisobutyl
`ether (isobutyl diglycol).
`
`[0057] Glycol ethers under the classification of propylene
`glycol ethers include propylene glycol monomethyl ether,
`dipropylene glycol monomethyl ether (PPG-2 methyl ether),
`tripropylene glycol monomethyl ether (PPG-3 methyl ether),
`propylene glycol n-propyl ether, dipropylene glycol n-pro(cid:173)
`pyl ether (PPG-2 propyl ether), propylene glycol monobutyl
`ether, dipropylene glycol monobutyl ether (PPG-2 butyl
`ether), propylene glycol monoisobutyl ether, and dipropy(cid:173)
`lene glycol dimethyl ether. In one embodiment of the
`invention the solvation enhancer is ethoxydiglycol. In
`another embodiment, the solvation enhancer is butoxydig(cid:173)
`lycol.
`
`[0058] A second group of organic solvents useful in the
`present invention includes the compounds classified as dials.
`A dial is an organic compound with two hydroxyl groups. It
`will be understood that an ether glycol as presented above
`may contain two hydroxyl groups and may therefore be
`classified as a dial. Dials suitable for use in the present
`invention include diethylene glycol, triethylene glycol, pro(cid:173)
`pylene glycol, propanediol, dipropylene glycol, butylene
`glycol, hexylene glycol, pentylene glycol, and isopentyldiol.
`
`[0059] Additional organic solvents suitable for use in the
`present invention that are moderately soluble to miscible in
`water include mono alcohols of the formula C1 to C10, and
`esters thereof including, but not limited to, dimethyl isos(cid:173)
`orbide, benzyl alcohol, triacetin, diacetin, ethanol, butyl
`
`alcohol, propylene carbonate, butylene carbonate, ethoxy(cid:173)
`diglycol acetate, 1-methyl-2-pyrrolidone, dimethylsulfox(cid:173)
`ide, ethoxydiglycol ace