(12) United States Patent
`Chen et al.
`
`USOO6267985B1
`(10) Patent No.:
`US 6,267,985 B1
`(45) Date of Patent:
`Jul. 31, 2001
`
`(54) CLEAR OIL-CONTAINING
`PHARMACEUTICAL COMPOSITIONS
`(75) Inventors: Feng-Jing Chen; Mahesh V. Patel,
`both of Salt Lake City, UT (US)
`(73) Assignee: Lipocine Inc., Salt Lake City, UT (US)
`(*) Notice:
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`(21) Appl. No.: 09/345,615
`(22) Filed:
`Jun. 30, 1999
`
`(51) Int. Cl. ............................... A61K 9/08; A61K 9/10;
`A61K 9/14; A61 K9/20: A61 K9/48
`
`(52) U.S. Cl. ......................... 424/451; 424/43; 424/195.1;
`424/433; 424/436; 424/441; 424/443; 424/455;
`424/456; 424/458; 424/463; 424/464; 424/465;
`424/489; 424/490; 514/772.2; 514/772.3;
`514/777; 514/778; 514/779; 514/781; 514/783;
`514/784; 514/785; 514/786; 514/937; 514/944
`
`(58) Field of Search ..................................... 424/451, 455,
`424/456, 436, 43, 430, 464, 489, 441, 449,
`423, 427, 434, 435, 443, 490, 458; 514/937,
`944
`
`(56)
`
`References Cited
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`3/1997 Walch et al. ........................... 514/11
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`5/1997 Nyqvist et al. ...................... 424/450
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`514/424
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`6/1997 Woo ...........
`... 424/452
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`... 424/455
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`8/1997 Modi et al. .......................... 424/400
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`... 424/450
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`... 424/452
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`1/1998 Yiv ....................................... 424/450
`
`
`
`
`
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`32.
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`5.948,825
`
`- -2
`
`2
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`3/1998 Hausheer et al. .................... 514/283
`3/1998 Jones et al. .......................... 514/731
`4/1998 Yesair ..........
`... 514/784
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`to t al
`3.
`10/1998 Stone ................................ 424/278.1
`1/1999 Bhalani et al. ...................... 424/450
`9/1999 Takahashi et al. ................... 514/937
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`O Clal. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`OTHER PUBLICATIONS
`Alvarez, F.J. and Stella, V.J., “The Role of Calcium Ions and
`Bile Salts on the Pancreatic Lipase-Catalyzed Hydrolysis of
`Triglyceride Emulsions Stabilized with Lecithin”, Pharma
`ceutical Research, 6(6), 449–457 (1989).
`Bates, T.R. and Sequeira, J.A., “Bioavailability of Micron
`ized Griseofulvin from Com Oil-in-Water Emulsion, Aque
`ouS Suspension, and Commercial Tablet Dosage Forms in
`Humans”, Journal of Pharmaceutical Sciences, 64(5),
`793–797 (1975).
`Bernkop-Schnürch, A., “The Use of Inhibitory Agents to
`Overcome the Enzymatic Barrier to Perorally Administered
`Therapeutic Peptides and Proteins, Journal of Controlled
`Release, 52, 1-16 (1998).
`Charman, W.N., Porter, C.J.H., Mithani, S., and Bressman,
`J.B., “Physicochemical and Physiological Mechanisms for
`the Effects of Food on Drug Absorption: The Role of Lipids
`and pH”, Journal of Pharmaceutical Sciences, 86(3),
`269-282 (1977).
`Gennaro, A.R., Remington's Pharmaceutical Science, Chap
`ter 20, 293–300 (1985).
`Horter, D. and Dressman, J .B., Influence of Physicochemi
`cal Properties on Dissolution of Drugs in the Gastrointesti
`nal Tract', Advanced Drug Delivery Reviews 25, 3-14
`(1977).
`Humberstone, A.J. and Charman, W.N. “Lipid-based
`Vehicles for the Oral Deli
`f Poorly Water Solubl
`encies, grine talleyery
`roorly water Souple
`Drugs”, Advanced Drug Delivery Reviews, 103–128 (1977).
`Hutchison, K., “Digestible Emulsions and Microemulsions
`for Optimum Oral Delivery of Hydrophobic Drugs”, Journ
`ées Galeniques, 67-74, (1994).
`(List continued on next page.)
`Primary Examiner-James M. Spear
`(74) Attorney, Agent, or Firm-Dianne E. Reed; Reed &
`ASSociates
`ABSTRACT
`(57)
`The present invention relates to pharmaceutical composi
`tions and methods for improved Solubilization of triglycer
`ides and improved delivery of therapeutic agents. Compo
`Sitions of the present invention include a triglyceride and a
`carrier, where the carrier is formed from a combination of at
`least two Surfactants, at least one of which is hydrophilic.
`Upon dilution with an aqueous Solvent, the composition
`forms a clear, aqueous dispersion of the triglyceride and
`Surfactants. An optional therapeutic agent can be incorpo
`rated into the composition, or can be co-administered with
`the composition. The invention also provides methods of
`enhancing triglyceride Solubility and methods of treatment
`with therapeutic agents using these compositions.
`
`184 Claims, No Drawings
`
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`
`

`

`US 6,267,985 B1
`Page 2
`
`OTHER PUBLICATIONS
`Johnson, L.R., “Gastrointestinal Physiology”, Department
`of Physiology, University of Texas Medical School, Houston,
`Texas, 25–26, 93, 106, 133–104, 136–137 (1997).
`LeCluyse, E.L.; Sutton, S.C., “In Vitro Models for Selection
`of Development Candidates. Permeability Studies to Define
`Mechanisms of Absorption Enhancement’, Advanced Drug
`Delivery Reviews, 23, 163–183 (1997).
`MacGregor, K.J. et al., “Influence of Lipolysis on Drug
`Absorption From the Gastro-intestinal Tract', Advanced
`Drug Delivery Reviews 25, 33–46 (1997).
`Pouton, C. W., “Formulation of Self-Emulsifying Drug
`Delivery Systems”, Advanced Drug Delivery Reviews 25,
`47-48 (1997).
`Reymond, J. and Sucker, H., “In Vitro Model for Ciclosporin
`Intestinal Absorption in Lipid Vehicles”, Pharmaceutical
`Research, 5(10), 677-679, Oct. 1987.
`
`Tarr, D.T. and Yalkowsky, S.H. “Enhanced Intestinal
`Absorption of Cyclosporine in Rats Through The Reduction
`of Emulsion Droplet Size', Pharmaceutical Research, 6(1),
`40–43 (1989).
`Wilson, C.G., O'Mahony, B., “The Behaviour of Fats and
`Oils in the Upper G.I. Tract', Bulletin Technique Gattefossé,
`No. 90, 13–18 (1997).
`Winne, D., “Dependence of Intestinal Absorption in Vivo on
`the Unstirred Layer”, Archives of Pharmacology, 304,
`175-181 (1978).
`Zhi, J., Rakhit, A., and Patel, I.H., “Effects of Dietary fat on
`Drug Absorption’, Clinical Pharmacology and Therapeu
`tics, 58(5), 487–491 (1995).
`
`* cited by examiner
`
`Purdue 2032
`Collegium v. Purdue, PGR2018-00048
`
`

`

`US 6,267,985 B1
`
`1
`CLEAR OL-CONTAINING
`PHARMACEUTICAL COMPOSITIONS
`
`FIELD OF THE INVENTION
`The present invention relates to drug and nutrient delivery
`Systems, and in particular to pharmaceutical compositions
`and methods for the improved solubilization of triglycerides
`and improved delivery of therapeutic agents.
`
`2
`the medical professional's ability to safely administer thera
`peutically effective dosages. In addition, when Such com
`positions are administered parenterally, the presence of large
`particles can block blood capillaries, further compromising
`patient Safety.
`A further disadvantage of conventional triglyceride
`containing compositions is the dependence of therapeutic
`agent absorption on the rate and extent of lipolysis. Although
`colloidal emulsion particles can transport therapeutic agents
`through the aqueous environment of the gastrointestinal
`tract, ultimately the triglyceride must be digested and the
`therapeutic agent must be released in order to be absorbed
`through the intestinal mucosa. The triglyceride carrier is
`emulsified by bile Salts and hydrolyzed, primarily by pan
`creatic lipase. The rate and extent of lipolysis, however, are
`dependent upon Several factors that are difficult to
`adequately control. For example, the amount and rate of bile
`Salt Secretion affect the lipolysis of the triglycerides, and the
`bile Salt Secretion can vary with Stomach contents, with
`metabolic abnormalities, and with functional changes of the
`liver, bile ducts, gallbladder and intestine. Lipase availabil
`ity in patients with decreased pancreatic Secretory function,
`Such as cystic fibrosis or chronic pancreatitis, may be
`undesirably low, resulting in a Slow and incomplete triglyc
`eride lipolysis. The activity of lipase is pH dependent, with
`deactivation occurring at about pH 3, So that the lipolysis
`rate will vary with Stomach contents, and may be insufficient
`in patients with gastric acid hyper-Secretion. Moreover,
`certain Surfactants commonly used in the preparation of
`pharmaceutical emulsions, Such as polyethoxylated castor
`oils, may themselves act as inhibitors of lipolysis. Although
`recent work Suggests that certain Surfactant combinations,
`when used in combination with digestible oils in emulsion
`preparations, can Substantially decrease the lipolysis
`inhibiting effect of Some common pharmaceutical Surfac
`tants (see, U.S. Pat. No. 5,645,856), such formulations are
`Still Subject to the other disadvantages of pharmaceutical
`emulsions and triglyceride-based formulations.
`Yet another approach is based on formation of “micro
`emulsions.” Like an emulsion, a microemulsion is a liquid
`dispersion of oil in water, Stabilized by Surfactants. Con
`ventional microemulsions, however, present Several Safety
`and efficiency problems. The amount of triglyceride that can
`be Solubilized in a conventional microemulsion is generally
`quite Small, resulting in a poor loading capacity. In order to
`Solubilize significant amounts of triglycerides, large
`amounts of hydrophilic Surfactant and/or Solvents must be
`used. These high concentrations of hydrophilic Surfactant
`and Solvents raise questions of Safety, Since the levels of
`hydrophilic Surfactant and Solvent needed can approach or
`exceed bioacceptable levels.
`Thus, there is a need for pharmaceutical compositions that
`overcome the limitations and Safety concerns of conven
`tional triglyceride-containing formulations, but without Suf
`fering from the disadvantages described above.
`SUMMARY OF THE INVENTION
`It is therefore an object of the present invention to provide
`pharmaceutical compositions capable of Solubilizing greater
`amounts of triglycerides in a homogeneous aqueous disper
`Sion.
`It is another object of the present invention to provide
`pharmaceutical compositions capable of Solubilizing thera
`peutically effective amounts of therapeutic agents, including
`pharmaceutical, nutritional, and cosmeceutical agents.
`It is another object of the invention to provide
`triglyceride-containing pharmaceutical compositions that
`are homogeneous and thermodynamically stable.
`
`15
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`
`BACKGROUND
`A wide variety of therapeutic agents, Such as drugs,
`nutritional agents, and cosmeceuticals, are conventionally
`formulated in oil/water emulsion Systems. These conven
`tional emulsions take advantage of the increased Solubility
`of many therapeutic agents in oils (triglycerides). Thus, one
`conventional approach is to Solubilize a therapeutic agent in
`a bioacceptable triglyceride Solvent, Such as a digestible
`vegetable oil, and disperse this oil phase in an aqueous
`Solution. The dispersion may be Stabilized by emulsifying
`agents and provided in emulsion form. Alternatively, the
`therapeutic agent can be provided in a water-free
`formulation, with an aqueous dispersion being formed in
`Vivo in the gastrointestinal environment. The properties of
`these oil-based formulations are determined by Such factors
`as the Size of the triglyceride/therapeutic agent colloidal
`particles and the presence or absence of Surfactant additives.
`In Simplest form, a triglyceride-containing formulation
`Suitable for delivering therapeutic agents through an aque
`ous environment is an oil-in-water emulsion. Such emul
`Sions contain the hydrophobic therapeutic agent Solubilized
`in an oil phase which is dispersed in an aqueous environment
`with the aid of a Surfactant. The Surfactant may be present
`in the oil-based formulation itself, or may be a compound
`provided in the gastrointestinal System, Such as bile Salts,
`which are known to be in Vivo emulsifying agents. The
`colloidal oil particles sizes are relatively large, ranging from
`Several hundred nanometers to Several microns in diameter,
`in a broad particle size distribution. Since the particle sizes
`are on the order of or greater than the wavelength range of
`Visible light, Such emulsions, when prepared in an emulsion
`dosage form, are visibly “cloudy' or “milky” to the naked
`eye.
`Although conventional triglyceride-based pharmaceutical
`compositions are useful in Solubilizing and delivering Some
`45
`therapeutic agents, Such compositions are Subject to a num
`ber of Significant limitations and disadvantages. Emulsions
`are thermodynamically unstable, and colloidal emulsion
`particles will spontaneously agglomerate, eventually leading
`to complete phase Separation. The tendency to agglomerate
`and phase Separate presents problems of Storage and
`handling, and increases the likelihood that pharmaceutical
`emulsions initially properly prepared will be in a leSS
`optimal, less effective, and poorly-characterized State upon
`ultimate administration to a patient. Uncharacterized degra
`dation is particularly disadvantageous, Since increased par
`ticle Size Slows the rate of transport of the colloidal particle
`and digestion of the oil component, and hence the rate and
`extent of absorption of the therapeutic agent. These prob
`lems lead to poorly-characterized and potentially harmful
`changes in the effective dosage received by the patient.
`Moreover, changes in colloidal emulsion particle Size are
`also believed to render absorption more Sensitive to and
`dependent upon conditions in the gastrointestinal tract, Such
`as pH, enzyme activity, bile components, and Stomach
`contents. Such uncertainty in the rate and extent of ultimate
`absorption of the therapeutic agent Severely compromises
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`3
`It is still another object of the invention to provide
`pharmaceutical compositions of a therapeutic agent that
`have decreased dependence upon lipolysis for bioabsorp
`tion.
`It is yet another object of the invention to provide phar
`maceutical compositions capable of increasing the rate and/
`or extent of bioabsorption of co-administered therapeutic
`agents.
`In accordance with these and other objects and features,
`the present invention provides pharmaceutical compositions
`for improved Solubilization of triglycerides, and improved
`delivery of therapeutic agents. It has been Surprisingly found
`that pharmaceutical compositions containing Significant
`amounts of triglycerides can be formed without the disad
`Vantages of conventional triglyceride-containing composi
`tions by using a combination of Surfactants and triglycerides
`in amounts Such that when the pharmaceutical composition
`is mixed with an aqueous Solution, a clear aqueous disper
`Sion is formed. Such compositions can be co-administered
`with a therapeutic agent to increase the rate and/or extend of
`bioabsorption of the therapeutic agent, or can be provided
`with a therapeutic agent in the preconcentrate composition
`or in the diluent Solution.
`In one embodiment, the present invention relates to phar
`maceutical compositions having a triglyceride and a carrier,
`the carrier including at least two Surfactants, at least one of
`which is hydrophilic. The triglyceride and Surfactants are
`present in amounts Such that upon mixing with an aqueous
`Solution, either in vitro or in Vivo, the composition forms a
`clear aqueous dispersion. In a particular aspect of this
`embodiment, the composition is capable of containing more
`triglyceride than can be Solubilized in a clear aqueous
`dispersion having only one Surfactant, the Surfactant being
`hydrophilic.
`In another embodiment, the present invention relates to
`pharmaceutical compositions having a triglyceride and a
`carrier, the carrier including at least one hydrophilic Surfac
`tant and at least one hydrophobic Surfactant. The triglyceride
`and Surfactants are present in amounts Such that upon
`mixing with an aqueous Solution, either in vitro or in Vivo,
`the composition forms a clear aqueous dispersion. In a
`particular aspect of this embodiment, the composition is
`capable of containing more triglyceride than can be Solubi
`lized in a clear aqueous dispersion having a hydrophilic
`Surfactant but not having a hydrophobic Surfactant.
`In another embodiment, the triglyceride itself can have
`therapeutic value as, for example, a nutritional oil, or
`absorption-promoting value as, for example, a long-chain
`triglyceride ("LCT, having fatty acid chains longer than
`Co and preferably C-C) or a medium-chain triglyceride
`(“MCT", having Co-Co fatty acid chains). Thus, in this
`embodiment, the present invention provides pharmaceutical
`compositions including a triglyceride having nutritional
`and/or absorption-promoting value, and a carrier. The carrier
`includes at least two Surfactants, at least one of which is
`hydrophilic. Optionally, the carrier can include at least one
`hydrophilic Surfactant and at least one hydrophobic Surfac
`tant. The triglyceride and Surfactants are present in amounts
`Such that upon dilution with an aqueous Solution, either in
`Vitro or in Vivo, the composition forms a clear aqueous
`dispersion.
`In another embodiment, the present invention relates to
`methods of increasing the amount of triglyceride that can be
`Solubilized in an aqueous System, by providing a composi
`tion including a triglyceride and a carrier, the carrier includ
`ing at least two Surfactants, at least one of which is
`
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`
`US 6,267,985 B1
`
`4
`hydrophilic, and dispersing the composition in an aqueous
`Solution So that a clear aqueous dispersion is formed. Within
`the clear aqueous dispersion, the triglyceride is capable of
`being Solubilized in an amount greater than the amount of
`the triglyceride that remains Solubilized in an aqueous
`dispersion of the triglyceride and a carrier having only one
`Surfactant and having the same total Surfactant concentra
`tion. Optionally, the carrier can include at least one hydro
`philic Surfactant and at least one hydrophobic Surfactant.
`In another aspect, the present invention relates to
`triglyceride-containing pharmaceutical compositions as
`described in the preceding embodiments, which further
`include a therapeutic agent. In particular embodiments, the
`therapeutic agent is a hydrophobic drug or a hydrophilic
`drug. In other embodiments, the therapeutic agent is a
`nutritional agent. In Still further embodiments, the therapeu
`tic agent is a cosmeceutical agent.
`In another embodiment, the present invention relates to
`methods of increasing the Solubilization of a therapeutic
`agent in a composition, by providing the therapeutic agent in
`a composition of the present invention.
`In another embodiment, the present invention relates to a
`pharmaceutical composition which includes a therapeutic
`agent, a triglyceride and a carrier. The carrier includes at
`least two Surfactants, at least one of which is hydrophilic.
`Optionally, the carrier includes at least one hydrophilic
`Surfactant and at least one hydrophobic Surfactant. The
`triglyceride, and Surfactants are present in amounts Such that
`upon dilution with an aqueous Solution, either in Vitro or in
`Vivo, the composition forms a clear aqueous dispersion. The
`therapeutic agent is present in two amounts, a first amount
`of the therapeutic agent Solubilized in the clear aqueous
`dispersion, and a Second amount of the therapeutic agent that
`remains non-Solubilized but dispersed.
`In another embodiment, the present invention relates to
`methods of increasing the rate and/or extent of absorption of
`therapeutic agents by administering to a patient a pharma
`ceutical composition of the present invention. In this
`embodiment, the therapeutic agent can be present in the
`pharmaceutical composition pre-concentrate, in the diluent,
`or in a Second pharmaceutical composition, Such as a
`conventional commercial formulation, which is
`co-administered with a pharmaceutical composition of the
`present invention.
`These and other objects and features of the present
`invention will become more fully apparent from the follow
`ing description and appended claims, or may be learned by
`the practice of the invention as Set forth hereinafter.
`DETAILED DESCRIPTION OF THE
`PREFERRED EMBODIMENTS
`The present invention overcomes the problems described
`above characteristic of conventional triglyceride-containing
`formulations by providing unique pharmaceutical composi
`tions which form clear aqueous dispersions upon mixing
`with an aqueous Solution. Surprisingly, the present inventors
`have found that compositions including triglycerides and a
`combination of Surfactants can Solubilize therapeutically
`effective amounts of therapeutic agents in homogeneous,
`Single-phase Systems which are thermodynamically stable
`and optically clear. The optical clarity is indicative of a very
`Small particle size within the aqueous dispersions, and this
`Small particle size Substantially reduces lipolysis depen
`dence of the rate of bioabsorption, and other disadvantages
`of conventional triglyceride-containing formulations. Use of
`these formulations is thus believed to result in an enhanced
`
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`

`US 6,267,985 B1
`
`6
`
`TABLE 1-continued
`
`Triglycerides
`
`S
`rate and/or extent of absorption of the therapeutic agent.
`Advantageously, the compositions of the present invention
`are Surprisingly able to Solubilize greater amounts of trig
`lycerides than conventional formulations, even when the
`total Surfactant concentration is the same as in a conven
`tional formulation.
`
`A. Pharmaceutical Compositions
`
`In one embodiment, the present invention provides a
`pharmaceutical composition including a triglyceride and a
`carrier. The carrier includes at least two Surfactants, at least
`one of which is a hydrophilic Surfactant. Optionally, the
`carrier includes at least one hydrophilic Surfactant and at
`least one hydrophobic Surfactant. The triglyceride and Sur
`factants are present in amounts Such that upon dilution with
`an aqueous Solution, either in vitro or in Vivo, the compo
`Sition forms a clear aqueous dispersion. It is a particular and
`Surprising feature of the present invention that the compo
`Sition is homogeneous and optically clear, despite the pres
`ence of Substantial amounts of triglycerides, thereby pro
`Viding Surprising and important advantages over
`conventional triglyceride-containing formulations.
`1. Triglycerides
`The compositions of the present invention include one or
`more pharmaceutically acceptable triglycerides. Examples
`of triglycerides Suitable for use in the present invention are
`shown in Table 1. In general, these triglycerides are readily
`available from commercial Sources. For Several
`triglycerides, representative commercial products and/or
`commercial Suppliers are listed.
`
`TABLE 1.
`
`Triglycerides
`
`Triglyceride
`
`Aceituno oil
`Almond oil
`
`Araehis oil
`Babassu oil
`Blackcurrant seed oil
`Borage oil
`Buffalo ground oil
`Candlenut oil
`Canola oil
`Caster oil
`Chinese vegetable tallow oil
`Cocoa butter
`Coconut oil
`Coffee seed oil
`Corn oil
`Cottonseed oil
`
`Crambe oil
`Cuphea species oil
`Evening primrose oil
`Grapeseed oil
`Groundnut oil
`Hemp seed oil
`Illipe butter
`Kapok seed oil
`Linseed oil
`Menhaden oil
`
`Mowrah butter
`Mustard seed oil
`Oiticica oil
`Olive oil
`Palm oil
`Palm kernel oil
`
`Commercial Source
`
`Super Refined Almond Oil
`(Croda)
`
`Lipex 108 (Abitec)
`
`Pureco 76 (Abitec)
`Super Refined Corn Oil (Croda)
`Super Refined Cottonseed Oil
`(Croda)
`
`Super Refined Menhaden Oil
`(Croda)
`
`Super Refined Olive Oil (Croda)
`
`Triglyceride
`
`Peanut oil
`
`Poppy seed oil
`Rapeseed oil
`Rice bran oil
`Safflower oil
`
`Sal fat
`Sesame oil
`
`15
`
`Shark liver oil
`
`Shea nut oil
`Soybean oil
`
`Stillingia oil
`Sunflower oil
`Tall oil
`Tea sead oil
`Tobacco seed oil
`Tung oil (China wood oil)
`Ucuhuba
`Vermonia oil
`Wheat germ oil
`
`Hydrogenated caster oil
`Hydrogenated coconut oil
`Hydrogenated cottonseed oil
`Hydrogenated palm oil
`
`Hydrogenated soybean oil
`
`Hydrogenated vegetable oil
`
`Hydrogenated cottonseed and
`caster oil
`Partially hydrogenated soybean
`oi
`Partially soy and cottonseed oil
`yceryl tributyrate
`yceryl tricaproate
`yceryl tricaprylate
`yceryl tricaprate
`yceryl trundecanoate
`yceryl trilaurate
`yceryl trimyristate
`yceryl tripalmitate
`yceryl tristearate
`yceryl triarcidate
`yceryl tri
`yceryl tripalmitoleate
`yceryl trioleate
`yceryl trili
`ycery
`yceryl tricaprylate/caprate
`
`Glyceryl tricaprylate/capratef
`
`Glyceryl tricaprylate/capratef
`
`Glyceryl tricaprylate/capratef
`Stearate
`Glyceryl tricaprylate/laurate?
`Stearate
`Glyceryl 1,2-caprylate-3-
`linoleate
`Glyceryl 12-caprate-3-stearate
`Glyceryl 1,2-laurate-3-myristate
`Glyceryl 1.2-myristate-3-laurate
`Glyceryl 1,3-palmitate-2-
`butyrate
`
`25
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Commercial Source
`
`Super Refined Peanut Oil
`(Croda)
`
`Super Refined Safflower Oil
`(Croda)
`Super Refined Sesame Oil
`(Croda)
`Super Refined Shark Liver Oil
`(Croda)
`Super Refined Soybean Oil
`(Croda)
`
`Super Refined Wheat Germ. Oil
`(Croda)
`Castorwax
`Pureco 100 (Abitec)
`Dritex C (Abitec)
`Dritex PST (Abitec); Softisan
`154 (Hils)
`Sterotex HM NF (Abitec):
`Dritex S (Abitec)
`Sterotex NF (Abitec): Hydrokote
`M (Abitec)
`Sterotex K (Abitec)
`Hydrokote AP5 (Abitec)
`
`Apex B (Abitec)
`(Sigma)
`(Sigma)
`(Sigma)
`Captex 1000 (Abitec)
`Captex 8227 (Abitec)
`(Sigma)
`Dynasan 114 (Hils)
`Dynasan 116 (Hils)
`Dynasan 118 (Hils)
`(Sigma)
`(Sigma)
`(Sigma)
`(Sigma)
`(Sigma)
`(Sigma)
`Captex 300 (Abitec); Captex 355
`(Abitec); Miglyol 810 (Hils);
`Miglyol 812 (Htils)
`Captex 350 (Abitec)
`Captex 810 (Abitec); Miglyol
`818 (Huls)
`Softisan 378 (Huls); (Larodan)
`
`(Larodan)
`
`(Larodan)
`
`(Larodan)
`(Larodan)
`(Larodan)
`(Larodan)
`
`Purdue 2032
`Collegium v. Purdue, PGR2018-00048
`
`

`

`US 6,267,985 B1
`
`7
`
`TABLE 1-continued
`
`Triglycerides
`
`Triglyceride
`Glyceryl 1,3-stearate-2-caprate
`Glyceryl 1.2-linoleate-3-
`caprylate
`
`Commercial Source
`(Larodan)
`(Larodan)
`
`Fractionated triglycerides, modified triglycerides, Syn
`thetic triglycerides, and mixtures of triglycerides are also
`within the scope of the invention.
`Preferred triglycerides include vegetable oils, fish oils,
`animal fats, hydrogenated vegetable oils, partially hydroge
`nated vegetable oils, medium and long-chain triglycerides,
`and Structured triglycerides. It should be appreciated that
`Several commercial Surfactant compositions contain Small to
`moderate amounts of triglycerides, typically as a result of
`incomplete reaction of a triglyceride Starting material in, for
`example, a transesterification reaction. Such commercial
`Surfactant compositions, while nominally referred to as
`“surfactants”, may be suitable to provide all or part of the
`triglyceride component for the compositions of the present
`invention. Examples of commercial Surfactant compositions
`containing triglycerides include Some members of the Sur
`factant families Gelucires (Gatte fosse), Maisines
`(Gattefosse), and Imwitors (Hils). Specific examples of
`these compositions are:
`Gelucire 44/14 (Saturated polyglycolized glycerides)
`Gelucire 50/13 (Saturated polyglycolized glycerides)
`Gelucire 53/10 (Saturated polyglycolized glycerides)
`Gelucire 33/01 (semi-synthetic triglycerides of C-Cls
`Saturated fatty acids)
`Gelucire 39/01 (semi-synthetic glycerides)
`other Gelucires, such as 37/06, 43/01, 35/10, 37/02,
`46/07, 48/09, 50/02, 62/05, etc.
`Maisine 35-I (linoleic glycerides)
`Imwitor 742 (caprylic/capric glycerides)
`Still other commercial Surfactant compositions having
`Significant triglyceride content are known to those skilled in
`the art. It should be appreciated that Such compositions,
`which contain triglycerides as well as Surfactants, may be
`Suitable to provide all or part of the triglyceride component
`of the compositions of the present invention, as well as all
`or part of the Surfactant component, as described below. Of
`course, none of the commonly known triglyceride
`containing commercial Surfactants alone provides the
`unique pharmaceutical compositions and characteristics as
`recited in the appended claims.
`Among the above-listed triglycerides, preferred triglyc
`erides include: almond oil; babasSu oil; borage oil; black
`currant Seed oil; canola oil; castor oil; coconut oil; corn oil;
`cottonseed oil; evening primrose oil; grapeseed oil; ground
`nut oil; mustard Seed oil, olive oil; palm oil, palm kernel oil;
`peanut oil; rapeseed oil; Safflower oil; Sesame oil; Shark liver
`oil, Soybean oil; Sunflower oil, hydrogenated castor oil;
`hydrogenated coconut oil, hydrogenated palm oil; hydroge
`nated Soybean oil, hydrogenated vegetable oil, hydroge
`nated cottonseed and castor oil, partially hydrogenated Soy
`bean oil, partially Soy and cottonseed oil; glyceryl
`tricaproate, glyceryl tricaprylate, glyceryl tricaprate, glyc
`eryl triundecanoate, glyceryl trilaurate; glyceryl trioleate;
`glyceryl trilinoleate; glyceryl trilinolenate, glyceryl
`tricaprylate/caprate; glyceryl tricaprylate/caprate/laurate;
`glyceryl tricaprylate/caprate/linoleate; and glyceryl
`
`1O
`
`15
`
`25
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`8
`tricaprylate/caprate/Stearate. Other preferred triglycerides
`are Saturated polyglycolized glycerides (Gelucire 44/14,
`Gelucire 50/13 and Gelucire 53/10), linoleic glycerides
`(Maisine 35-I), and caprylic/capric glycerides (Im witor
`742).
`Among the preferred triglycerides, more preferred trig
`lycerides include: coconut oil; corn oil, olive oil; palm oil;
`peanut oil; Safflower oil; Sesame oil, Soybean oil, hydroge
`nated castor oil, hydrogenated coconut oil, partially hydro
`genated Soybean oil; glyceryl tricaprate, glyceryl trilaurate;
`glyceryl trioleate; glyceryl trilinoleate; glyceryl tricaprylate/
`caprate, glyceryl tricaprylate/caprate/laurate, glyceryl
`tricaprylate/caprate/linoleate; glyceryl tricaprylate/caprate/
`Stearate; Saturated polyglycolized glycerides (Gelucire
`44/14, Gelucire 14 50/13 and Gelucire 53/10); linoleic
`glycerides (Maisine 35-I); and caprylic/capric glycerides
`(Imwitor 742).
`2. Surfactants
`The carrier includes a combination of Surfactants, at least
`one of which is a hydrophilic Surfactant, with the remaining
`Surfactant or Surfactants being hydrophilic or hydrophobic.
`As is well known in the art, the terms “hydrophilic' and
`“hydrophobic' are relative terms. To function as a
`Surfactant, a compound must necessarily include polar or
`charged hydrophilic moieties as well as non-polar hydro
`phobic (lipophilic) moieties; i.e., a Surfactant compound
`must be amphiphilic. An empirical parameter commonly
`used to characterize the relative hydrophilicity and hydro
`phobicity of non-ionic amphiphilic compounds is the
`hydrophilic-lipophilic balance (the “HLB' value). Surfac
`tants with lower HLB values are more hydrophobic, and
`have greater Solubility in oils, whereas Surfactants with
`higher HLB values are more hydrophilic, and have greater
`Solubility in aqueous Solutions.
`Using HLB values as a rough guide, hydrophilic Surfac
`tants are generally considered to be those compounds having
`an HLB value greater than about 10, as well as anionic,
`cationic, or Zwitterionic compounds for which the HLB
`Scale is not generally applicable. Similarly, hydrophobic
`Surfactants are compounds having an HLB value less than
`about 10.
`It should be appreciated tha