United States Patent
`Coapman
`
`[19)
`
`[75]
`
`[54] PROCESS FOR SOLUBILIZING
`DIFFICULTY SOLUBLE
`PHARMACEUTICAL ACTIVES
`Inventor: Scott D. Coapman, New Haven,
`Conn.
`[73] Assignee: Richrdson·Vicks Inc., Shelton, Conn.
`[21] Appl. No.: 722,056
`(22] Filed:
`Jun. 27, 1991
`[51]
`Int. CJ.s ..................... A61K 31/44; A61K 31/40;
`A61K 31/225; A61K 31/19; A61K 31/135;
`A61K 31/075
`[52] U.S. Cl. .................................... 514/629; 514/289;
`514/420; 514/343; 514/357; 514/548; 514/570;
`514/648; 514/653; 5141718; 5141772
`[58) Field of Search .................. 424/80, 456; 514/289,
`514/629, 653, 772
`
`[56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`3,851.051 11/1974 Miske! et al. ......................... 424/37
`4.067.960 1/1978 Fadda .................................... 424/14
`4.198.391 4/1980 Grainger ............................... 424/37
`4,690.823 9/1987 Lohrer et al. ....................... 424/456
`4.744,988 5/1988 Brox .................................... 424/456
`4,764.378 8/1988 Keith et al. ......................... 424/435
`4.780.316 10/1988 Brox .................................... 424/456
`4.820.522 4/1989 Radebaugh et al. ................ 424/468
`4.857.312 8/1989 Hegasy et al. ........................ 424/80
`4,888,239 12/1989 Brox ................................. 428/402.2
`4.968.509 11/1990 Radebaugh et al. ................ 424/470
`5.006.595 4/1991 Smith et al. ......................... 524/548
`
`FOREIGN PATENT DOCUMENTS
`CA(8):59913b 10/1982 Japan .
`57-01096J/47 10/1982 Japan .
`2185887 8/1987 United Kingdom .
`
`111111111111111111111111111111111111111111111111111111111111111111111111111
`US005!41961A
`5,141,961
`Patent Number:
`Date of Patent: Aug. 25, 1992
`
`[II)
`
`[45]
`
`OTHER PUBLICATIONS
`D. Q. M. Craig, "Polyethylene Glycols and Drug Re(cid:173)
`lease", Drug Dev. and Industrial Pharmacy, 16( 17), pp.
`2501-2526 (1990).
`J. E. Hilton et al., "The Effect of Wetting Agents on the
`Dissolution of Indomethacin Solid Dispersion Sys(cid:173)
`tems", Int J of Pharm, 31 pp. 157-164, (1986).
`L. Lachman et al., "Soft Gelatin Capsules", The The(cid:173)
`ory and Practice of Industrial Pharmacy, (Lea &
`Febiger, Phil.) pp. 398-412 (1986).
`H. Seager, ''Soft Gelatin Capsules: A Solution to Many
`Tableting Problems", Pharmaceutical Technology,
`Sep. 1985:
`RP Sherer Technical Data Bulletin, "Scherersol TM
`The Best Solution for Better Drug Absorption".
`Primary Examiner-Frederick E. Waddell
`Assistant Examiner-Kimberly Jordan
`Attorney, Agent, or Firm-Anthony D. Sabatelli; David
`K. Dabbiere; Douglas C. Mohl
`[57)
`ABSTRACT
`The present invention relates to a process for solubiliz(cid:173)
`ing at least one difficultly soluble pharmaceutical active
`in a mixture of polyethylene glycol and polyvinylpyr(cid:173)
`rolidone. The process does not require water as a sol(cid:173)
`vent or the use of a heating step. In further embodi(cid:173)
`ments, the present invention also relates to a process for
`encapsulating these solubilized pharmaceutical compo(cid:173)
`sitions within soft gelatin shells, which are preferably
`transparent. Both the resulting compositions and their
`capsules provide an effective means for oral delivery of
`a wide variety of difficultly soluble pharmaceutical
`actives.
`
`24 Claims, No Drawings
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1012, Pg. 1 of 9
`
`

`

`PROCESS FOR SOLUBILIZING DIFFICULTY
`SOLUBLE PHARMACEUTICAL ACilVES
`
`TECHNICAL FIELD
`The present invention relates to a process for solubi(cid:173)
`lizing at least one difficulty soluble pharmaceutical
`active in a mixture of polyethylene glycol and polyvi(cid:173)
`nylpyrrolidone. In further embodiments, the present
`invention also relates to a process for encapsulating
`these solubilized pharmaceutical compositions within
`soft gelatin shells, which are optionally transparent.
`Both the resulting compositions and their capsules pro(cid:173)
`vide an effective means for oral delivery of a wide vari(cid:173)
`ety of difficulty soluble pharmaceutical actives.
`
`BACKGROUND OF THE INVENTION
`Liquid, and especially concentrated liquid pharma(cid:173)
`ceutical compositions offer many advantages over solid
`compositions. Liquids are easy to swallow and provide 20
`an excellent vehicle for the uniform delivery of pharma(cid:173)
`ceutical actives. Liquids provide a rapid onset of phar(cid:173)
`macologic action. since the composition does not first
`have to disintegrate and dissolve in the gastrointestinal
`tract. Concentrated liquid compositions are ideally 25
`suited for encapsulation within a soft gelatin shell, to
`provide a portable and easy-to-swallow soft, flexible
`capsule. Encapsulation would also permit the accurate
`and uniform delivery of a unit dose of a pharmaceutical
`active, an advantage which becomes especially impor- 30
`tant when relatively small amounts of an active are to be
`delivered. Additionally, soft gelatin capsules are aes(cid:173)
`thetically appealed (especialiy when filled with a trans(cid:173)
`parent liquid) and can be manufactured in a wide vari(cid:173)
`ety of sizes. shapes, and colors.
`However, despite these advantages of liquid compo(cid:173)
`sitions. it is not always possible to prepare a liquid com(cid:173)
`position of the desired pharmaceutical active. Many
`pharmaceutical actives are poorly soluble and therefore
`require relatively large volumes of solvent for dissolu- 40
`tion . Also, the choice of solvents available for use in
`liquid compositions is limited by safety, compatibility,
`stability, and economic concerns. Furthermore, the use
`of large volumes of solvents for solubilizing pharmaceu(cid:173)
`tical actives is undesirable because the resulting solu- 45
`tions would be so dilute as to require impractically large
`dosages for delivering a
`therapeutically effective
`amount of active. It would thus be difficult, if not im(cid:173)
`possible, to encapsulate such large volumes into only
`one or two gelatin capsules and yet have them be of a SO
`reasonable size for easy swallowing.
`One approach to overcoming these solubility prob(cid:173)
`lems has been to incorporate water, water-miscible
`co-solvents, and surfactants into the compositions. See,
`U.S. Pat. No. 4,794,1 17, to Corbiere, issued Dec. 27, SS
`I 988 which discloses the solubilization of hydrophobic
`pharmaceuticals in aqueous solutions of polyethylene
`glycol at controlled pH; U.S. Pat. No. 4,690,823, to
`Lohner at al, issued Sep. I, 1987 which discloses the
`solubilization of ibuprofen in a mixture of polyethylene 60
`glycol and a surfactant; U.S. Pat. No. 3,784,684, to
`Bossert et al., issued Jan. 8, 1974 which discloses the
`solubilization of a pharmaceutical active in a mixture of
`polyethylene glycol and an alcohol having 2-8 carbons
`and 1-3 hydroxy groups; PCT Application No. 65
`W088/02625, to Yu et al., published Apr. 21, 1988
`which discloses the solubilization of an ionized or part(cid:173)
`ly-ionized pharmaceutical active in a mixture of water,
`
`1
`
`5,141,961
`
`2
`polyethylene glycol, and polyvinylpyrrolidone; and
`European Patent Application No. 152,292, to Rogers,
`published Aug. 21, 1985 which discloses acetaminophen
`formulations containing polyethylene glycol, an acrylic
`5 acid resin, and a surfactant.
`In many instances it may not be possible or desirable
`to incorporate water. water-miscible co-solvents, or
`surfactants into a pharmaceutical composition. For ex(cid:173)
`ample, water-miscible co-solvents, such as ethanol,
`10 have the disadvantage of being relatively volatile,
`thereby resulting in concentration changes in the ac(cid:173)
`tives over time. Also, these co-solvents may not be
`compatible with the desired pharmaceutical actives. A
`more important disadvantage of water and volatile wa-
`15 ter-miscible co-solvents is that they are incompatible
`with soft gelatin capsules. Even though it may be possi(cid:173)
`ble to prepare soft gelatin capsules containing these
`solvents, over time the capsules gradually soften and
`deform, and develop leaks as these solvents dissolve the
`soft gelatin shell. Thus, it would be highly desirable to
`develop a solubilization process which does not require
`the use of water; and in processes where water-miscible
`co-solvents are used, it would be highly desirable to
`develop a process in which the water-miscible solvents
`are ultimately removed from the final compositions.
`Previous investigators have attempted to circumvent
`these incompatibility problems by modifying the com(cid:173)
`position of the capsule shell. For example, U.S. Pat. No.
`3,865,603, to Szymanski et al., issued Feb. 1 I, 1975 dis(cid:173)
`closes gelatin compositions which are extended with
`chemically modified fluidity starches; 'U.S. Pat. No.
`2,580,683, to Kreuger, issued Jan. I, 1952 discloses gela(cid:173)
`tin compositions modified by the addition of non-hydro-
`35 scopic water soluble substances; and Japanese Pat. No.
`84044096, to Morishita, issued Jan. 26, 1984 discloses
`gelatin shells modified with tannic acid, and sugar and(cid:173)
`/or sugar derivatives. However, it may not always be
`desirable, feasible or economical to modify the soft
`gelatin shell with such additives. Thus, it would be
`highly desirable to find a solubilizing system for phar(cid:173)
`maceutical actives which would also be compatible
`with soft gelatin shells.
`Many processes for solubilizing pharmaceutical ac(cid:173)
`tives employ heat. However, heating the mixture is not
`always feasible or desirable because of stability con(cid:173)
`cerns and the additional equipment, time, and costs
`associated with utilizing a heating process. Thus, it
`would be highly desirable to develop a solubilization
`process not requiring the use of heat.
`The solubilization process of the present invention
`overcomes the disadvantages of the prior art by not
`requiring the use of water as a solvent, except for the
`minor amounts of water normally present in the materi(cid:173)
`als employed and/or which is absorbed from the envi(cid:173)
`ronment. Thus, the concentrated pharmaceutical com-
`positions of the instant invention are substantially free
`of water. Importantly, the process of the present inven(cid:173)
`tion does not require a heating step.
`It is therefore an object of the present invention to
`provide a process for solubilizing difficulty soluble
`pharmaceutical actives. Another object of the present
`invention is to provide a solubilization process which
`does not require water as a solvent or the use of a heat(cid:173)
`ing step. A further object of the present invention is to
`provide a process for preparing soft gelatin capsules
`containing a solution of a difficulty soluble pharmaceu(cid:173)
`tical active, in which the soft gelatin shell is optionally
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1012, Pg. 2 of 9
`
`

`

`3
`transparent. A still further object of the present inven(cid:173)
`tion is to provide pharmaceutical compositions contain(cid:173)
`ing difficulty soluble pharmaceutical actives. As even
`further object of the present invention is to provide soft
`gelatin capsules containing a solution of a difficulty 5
`soluble pharmaceutical active, in which the soft gelatin
`shell is optionally transparent.
`These and other objects of this invention will become
`apparent in light of the following disclosure.
`
`5,141,961
`
`4
`Concentrated Liquid Pharmaceutical Compositions
`The highly concentrated liquid pharmaceutical com(cid:173)
`positions of the present invention comprise the follow(cid:173)
`ing essential, as well as optional, components.
`
`Polyethylene Glycol
`An essential component of the present compositions
`is a polyethylene glycol. Polyethylene glycols generally
`10 are clear, viscous liquids or white solids which are solu(cid:173)
`ble in water and many organic solvents. These polymers
`correspond to the general formula:
`
`15
`
`SUMMARY OF THE INVENTION
`The present invention relates to a process not requir(cid:173)
`ing the use of heat or surfactants for solubilizing diffi(cid:173)
`culty soluble pharmaceutical actives, comprising the
`where n is greater than or equal to 4. Polyethylene
`steps of:
`glycols are described in G. M. Powell, III in Handbook
`(a) combining and mixing until dissolved
`of Water-Soluble Gums & Resins, R. L. Division, Ed .
`(i) from about I% to about 40% of at least one diffi-
`(McGraw-Hill, New York, 1980) pp. 18/1-18/31, this
`.. culty soluble pharmaceutical active,
`(n) from about 20% to about 70% of a polyethylene 20 reference being incorporated herein by reference in its
`... glycol,
`.
`entirety. Polyethylene glycols, which are also known as
`(m) from about I o/c to about 28% of a polyvmylpyr-
`"PEGs" or "polyoxyethylenes", are designated by both
`rolidone, and
`their average molecular weight range and their average
`(iv) from about I o/c to about SO% of a solvent selected
`"n" value as in the above designated formula. For exam-
`from the group consisting of monohydric alcohols 25 pie, polyethylene glycol 400, which is also known by
`the CTF A designation, PEG-8, has an average molecu-
`having from 1 to 4 carbon atoms and mixtures
`Jar weight range from 38~20 and an average value of
`thereof,
`wherein the ratio of said polyethylene glycol to said
`n between 8.2 and 9.1. See CTFA Cosmetic Ingredient
`polyvinylpyrrolidone is at least about 2.5: I; and
`Dictionary, Third Edition (1982), pp. 201-203; and The
`(b) evaporating said solvent to obtain a composition 30 Merck Index, Tenth Edition, entry 7441, p. 1092 (1983);
`containing from about 0.1 o/c to about 6o/c by weight
`these two references being incorporated herein by ref-
`of said solvent and from about 1.25% to about SOo/c
`erence in their entirety.
`of said difficulty soluble pharmaceutical active.
`The polyethylene glycols useful herein are those
`The present invention also relates to a process for
`which are liquids at room temperature or have a melt-
`preparing soft gelatin capsules containing a solution of a 35 ing point slightly thereabove. Preferred are the polyeth-
`difficulty soluble pharmaceutical active, and to the
`ylene glycols having a molecular weight range from
`about 300 to about 1000 and corresponding n values
`compositions and the filled capsules themselves.
`All percentages and ratios used herein are by weight
`from about 6 to abo~t 20. More prefern~d are the poly-
`and all measurements are at 25° C.. unless otherwise
`ethylene glycols havmg a molecular wetght range from
`40 about 400 to about 1000 and corresponding n values
`indicated.
`from about 8 to about 20. Most preferred are the poly(cid:173)
`DETAILED DESCRIPTION OF THE
`ethylene glycols having a molecular weight range from
`INVENTION
`about 600 to about 1000 and corresponding n values
`from about 12 to about 20. Most especially preferred is
`The term "difficulty soluble pharmaceutical active",
`as used herein, describes an active having a solubility of 45 a polyethylene glycol having a molecular weight of
`Jess than or equal to 1 o/c by weight in water at 2So c.
`about 600 and a corresponding n value of about 12.
`This term is defined to also include the descriptive Moreover, mixtures of two or more polyethylene gly-
`term~ "sparingly soluble"; "slightly soluble"; "very
`cols of different average molecular weight range or n
`value can also be employed in the present invention.
`slightly soluble"; "practically insoluble, or insoluble"; 50 Liquid and low-melting polyethylene glycols are com-
`mercially available from Union Carbide (Danbury,
`and their equivalents as defined in the USP XXII, p.8
`(1990), this reference being incorporated herein by ref-
`Conn.) under the Carbowax ® trademark. See "Car-
`erence in its entirety.
`bowax ®Polyethylene Glycols", Union Carbide Tech-
`The term "substantially free of water", as used
`nical Bulletin f-4772M-ICD 11!86-20M, this reference
`herein, describes highly concentrated pharmaceutical 55 being incorporated herein by reference in its entirety.
`Polyethylene glycols having an average molecular
`compositions which, as initially prepared, do not con-
`tain any water, except for the minor amounts of water
`weight below about 300 are not desirable for use in the
`normally present in the materials employed in their
`instant invention since such polyethylene glycols tend
`preparation and/or which is gradually absorbed from
`to diffuse into, plasticize, and ultimately disrupt the soft
`the environment or the optional gelatin shell; i.e., less 60 gelatin shells which can be employed to encapsulate the
`than from about 0.1% to about 8% water, preferably
`compositions described herein.
`less than from about 0.1% to about 6% water, more
`The process for preparing the highly concentrated
`preferably less than from about 0.1 o/c to about 4% wa-
`liquid compositions of the present invention comprises
`ter, and most preferably less than from about 0.1% to
`adding from about 20% to about 70% polyethylene
`about 2% water. The term "as initially prepared", as 65 glycol, more preferably from about 30% to about 60%,
`and most preferably from about 40% to about SO%.
`used herein, is defined to mean the period of time from
`when the evaporation step is completed to about S min-
`After the evaporation step, the resulting highly con-
`centrated liquid compositions of the present invention
`utes thereafter.
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1012, Pg. 3 of 9
`
`

`

`5,141,961
`
`5
`comprise from about 25% to about 87.5% polyethylene
`glycol, more preferably from about 37.5% to about
`75%, and most preferably from about 50% to about
`75%.
`
`Polyvinylpyrrolidone
`An essential component of the present compositions
`is polyvinylpyrrolidone ("PVP"), which is a polymer of
`N-vinyl-2-pyrrolidone having the following formula:
`
`6
`1.25% to about 12.5%, and most preferably from about
`1.25% to about 6.25%.
`An important requirement of the processes and com(cid:173)
`positions of the instant invention is that the polyethyl-
`5 ene glycol component(s) and the polyvinylpyrrolidone
`component(s) are present in a proper ratio. Preferably,
`the ratio of the total amount of polyethylene glycol to
`polyvinylpyrrolidone should be at least about 2.5:1.
`
`10
`
`Difficulty Soluble Pharmaceutical Actives
`The compositions of the instant invention contain at
`least one difficulty soluble pharmaceutical active as an
`essential component. In general, these actives have a
`solubility less than or equal to about 1 percent by
`15 weight in water at 25" C. Useful classes of pharmaceuti(cid:173)
`cally-active compounds which can be incorporated into
`the present compositions include analgesics; anti-in(cid:173)
`flammatory agents, anti-pyretics, calcium channel
`blockers, beta-blockers, antibacterials, antidepressants,
`antidiabetics, anti-emetics, antihistamines, cerebral stim(cid:173)
`ulants, sedatives, anti-parasitics, expectorants, diuretics,
`decongestants, antitussives, muscle relaxants, anit-Par(cid:173)
`kinsonian agents, bronchodilators, cardiotonics, antibi-
`otics, antivirals, nutritional supplements (such as vita(cid:173)
`mins, minerals, fatty acids, amino acids, and the like),
`and mixtures thereof. Difficulty soluble pharmaceutical
`actives selected from the non-narcotic analgesics/non(cid:173)
`steroidaL anti-inflammatory drugs are especially useful
`in the present invention. Examples of such drugs are
`disclosed in U.S. Pat. No. 4,522,828, to Sunshine et al.,
`issued Jun. II, 1985; this patent being incorporated
`herein by reference in its entirety.
`Examples of preferred difficulty soluble pharmaceuti(cid:173)
`cal actives useful in the present invention include, but
`are not limited to, acetaminophen, acetylsalicylic acid,
`ibuprofen, fenbuprofen, fenoprofen, flurbiprofen, indo(cid:173)
`methacin, ketoprofen, naproxen, their pharmaceutical(cid:173)
`ly-acceptable salts, and mixtures thereof. Acetamino-
`phen is especially preferred for use in the compositions
`of the present invention.
`The process for preparing the highly concentrated
`liquid compositions of the instant invention comprises
`adding from about I% to about 40% of a difficulty
`soluble pharmaceutical active, more preferably from
`about 15% to about 35%, and most preferably from
`about 20% to about 30%.
`After the evaporation step, the resulting highly con(cid:173)
`centrated liquid compositions of the instant invention
`comprise from about 1.25% to about 50% of a difficulty
`soluble pharmaceutical active, more preferably from
`about 18.75% to about 43.75%, and most preferably
`from about 25% to about 37.5%.
`
`Solvents
`A solvent selected from the group consisting of the
`monohydric alcohols having from one to four carbon
`atoms, and mixtures thereof, is an essential component
`of the processes of the instant invention. A sufficient
`quantity of solvent is utilized to aid in the solubilization
`of the essential components. By "sufficient" is means a
`quantity of solvent that will ensure solubility of the
`components of the composition and yet not dilute the
`composition to the point where it occupies an unreason(cid:173)
`ably large volume. After mixing and solubilization of
`the components of the instant invention, the solvent is
`removed using standard evaporation techniques until
`the composition is substantially free from solvent. The
`
`Polyvinylpyrrolidones are described in L. Blecher et al.
`in Handbook of Water-Soluble Gums & Resins, R. L.
`Davidson, Ed. (McGraw-Hill, New York, 1980) pp. 20
`21/1-21/21, this reference being incorporated herein by
`reference in its entirety. Polyvinylpyrrolidone has dif(cid:173)
`ferent solubility characteristics based on its polymeric
`structure. Long-chain polyvinylpyrrolidone, which is
`also known as povidone, has good solubility in water 25
`and a number of organic solvents. Cross-linked polyvi(cid:173)
`nylpyrrolidone, which is also known as crospovidone, is
`insoluble in virtually all common solvents. Both the
`soluble and insoluble forms of polyvinylpyrrolidone are
`commercially available from GAF Chemicals Com- 30
`pany (Wayne, N.J.) under the Plasdone ® and Poly(cid:173)
`plasdone ® trademarks, respectively, and from BASF
`Aktiengesellschaft (Ludwigshafen, Germany) under the
`Kollidon ® trademark. Soluble forms of polyvinylpyr(cid:173)
`rolidone include Plasdone ® K-25, Plasdone ® K- 35
`26/28, Plasdone ® K-29/32, Plasdone ® C-15, Plasdo-
`ne ® C-30, Plasdone ® C-90, Kollidon ® 12 PF, Kol(cid:173)
`lidon ® 17 PF, Kollidon ® 25, Kollidon ® 30, and
`Kollidon ® 90. Insoluble forms of polyvinylpyrroli(cid:173)
`done include Polyplasdone XLR, Polyplasdone XLRJO, 40
`Kollidon ® CL, and Kollidon ® CL-M. See "Tablet(cid:173)
`ing With Plasdone @", GAF Technical Bulletin 2302-
`IIOR I
`(1986); "Polyplasdone XLR, Polyplasdone
`XLRIO", GAF Technical Bulletin 2302-099 R2 (1984);
`and "Kollidon ®Grades, Polyvinylpyrrolidone for the 45
`Pharmaceutical Industry", BASF Technical Bulletin
`MEF 129e, Register 2, May 1986 (Bn); these references
`being incorporated herein by reference in their entirety.
`The soluble forms of polyvinylpyrrolidone are pre(cid:173)
`ferred for use in the present invention. Preferred are so
`soluble polyvinylpyrrolidones having an average mo(cid:173)
`lecular weight in the range from about 2900 to about
`I, 100,000; more preferred are those having an average
`molecular weight in the range from about 9000 to about
`45,000; and most preferred are those having an average 55
`molecular weight of about 29,000. Moreover, mixtures
`of two or more soluble polyvinylpyrrolidones of differ(cid:173)
`ent average molecular weight can be employed.
`The process for preparing the highly concentrated
`liquid compositions of the instant invention comprises 60
`adding from about I% to about 28% of a soluble polyvi(cid:173)
`nylpyrrolidone, more preferably from about 1% to
`about 10%, and most preferably from about I% to
`about 5%.
`After the evaporation step, the resulting highly con- 65
`centrated liquid compositions of the instant invention
`comprise from about 1.25% to about 35% of a soluble
`polyvinylpyrrolidone, more preferably from about
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1012, Pg. 4 of 9
`
`

`

`5,141,961
`
`8
`ings, flavorings, preservatives, lubricants, flow-enhanc(cid:173)
`ers, filling aids, antioxidants, essences, and other aes(cid:173)
`thetically pleasing components.
`
`7
`term "substantially free from solvent" is herein defined
`to mean that the compositions of the present invention
`comprise within after about 5 minutes of the evapora(cid:173)
`tion step no more than from about 0.1% to about 6% of
`solvent after the evaporation step. Ethanol is most pre- S
`ferred as the solvent for use in the processes of the
`instant invention.
`The process for preparing the highly concentrated
`liquid compositions of the im;tant invention comprises
`adding from about I% to about 50% of solvent, more to
`preferably from about 5% to about 40%, and most
`preferably from about 10% to about 30%.
`After the evaporation step, the resulting highly con(cid:173)
`centrated liquid compositions of the instant invention
`comprise no more that from about 0.1% to about 6% 15
`solvent.
`
`Process for Solubilizing Difficulty Soluble
`Pharmaceutical Actives
`The highly concentrated liquid pharmaceutical com(cid:173)
`positions are prepared using art-recognized principles
`and methodologies in mixing the ingredients together
`and in choosing the type of mixing equipment to be
`used. In a preferred manner of execution, the difficulty
`soluble pharmaceutical active, polyethylene glycol,
`polyvinylpyrrolidone, and solvent are combined and
`mixed until dissolved to form a homogeneous solution.
`Any optional components can either be added initially
`or after the essential components are combined.
`Next, the solvent is removed from the resulting ho(cid:173)
`mogeneous solution until the residual amount of solvent
`is present at no more than from about 0..1 percent to
`about 6 percent by weight of the composition. The
`solvents can be removed using any art-recognized evap(cid:173)
`oration techniques including, but not limited to, rotary
`evaporation, spray-drying, flash evaporation, film evap(cid:173)
`oration, freeze-drying, thin film evaporation, forced
`circulation evaporation, wiped film evaporation, falling
`film evaporation, and the like. The resulting solution of
`the difficulty soluble pharmaceutical active, and any
`optional components, is substantially free from the
`added alcoholic solvent, i.e., contains no more than
`from about 0.1 percent to about 6 percent by weight of
`solvent. This resulting solution is suitable for encapsula(cid:173)
`tion in a soft gelatin capsule using standard encapsula(cid:173)
`tion techniques.
`
`Additional Pharmaceutical Actives
`The compositions of the instant invention can also
`contain one or more additional pharmaceutical actives 20
`having a solubility greater than the difficulty soluble
`pharmaceutical actives described above. In general,
`these actives have a solubility greater than about I per(cid:173)
`cent by weight in water at 25• C. Useful classes of addi(cid:173)
`tional pharmaceutically-active compounds include anal- 25
`gesics, anti-inflammatory agents, antipyretics, calcium
`channel blockers. beta-blockers, antibacterials, antide(cid:173)
`pressants, antidiabetics, anti-emetics, antihistamines,
`cerebral stimulants. sedatives, anti-parasitics, expecto(cid:173)
`rants. diuretics, decongestants. antitussives, muscle re- 30
`laxants, anti-Parkinsonian agents, bronchodilators, car(cid:173)
`diotonics. antibiotics, antivirals, nutritional supplements
`(such as vitamins, minerals, fatty acids, amino acids. and
`the like), and mixtures thereof.
`Examples of additional pharmaceutical actives useful 35
`in the present invention include, but are not limited to,
`pseudoephedrine and its salts such as pseudoephedrine
`hydrochloride; dextromethorphan and its salts such as
`dextromethorphan hydrobromide: doxylamine and its
`salts such as doxylamine succinate; phenindamine and 40
`its salt~ such as phenindamine hydrogen tartrate; pheni(cid:173)
`ramine and its salts such as pheniramine maleate; chlor(cid:173)
`pheniramine and its salts such as chlorpheniramine ma(cid:173)
`leate: ephedrine and its salts such as ephedrine sulfate;
`Gelatin
`triprolidine and its salts such as triprolidine hydrochlo- 45
`Gelatin is an essential component of the soft gelatin
`ride: diphenhydramine and it salts such as diphenhydra-
`shells of the instant invention. The starting gelatin mate-
`mine hydrochloride, diphenhydramine citrate, and de-
`rial used in the manufacture of soft capsules is obtained
`phenhydramine 8-chlorotheophyllinate; phenyltoxyla-
`by the partial hydrolysis of collagenous material, such
`mine and its salts; guaifenesin; phenylpropanolamine
`hydrochloride; and mixtures thereof. Preferred addi- 50 as the skin, white connective tissues, or bones of ani-
`tiona! pharmaceutical actives are dextromethorphan
`mals. Gelatin material can be classified as Type A gela-
`tin, which_ is obtained from the acid-processing of por-
`hydrobromide, doxylamine succinate, pseudoephedrine
`hydrochloride, chlorpheniramine maleate, guaifenesin,
`cine skins and exhibits an isoelectric point between pH
`7 and pH 9; and Type B gelatin, which is obtained from
`triprolidine hydrochloride, diphenydramine hydrochlo-
`ride and mixtures thereof.
`55 the alkaline-processing of bone and animal (bovine)
`skins and exhibits an isoelectric point between pH 4.7
`The process for preparing the highly concentrated
`liquid compositions of the instant invention optionally
`and pH 5.2. Blends of Type A and Type B gelatins can
`comprises adding from about 0.5% to about 20% of a
`be used to obtain a gelatin with the requisite viscosity
`second pharmaceutical active, or mixtures thereof.
`and bloom strength characteristics for capsule manufac-
`After the evaporation step, the resulting highly con- 60 ture. Gelatin suitable for capsule manufacture is com-
`centrated liquid compositions of the instant invention
`mercially available from the Sigma Chemical Company,
`St. Louis, Mo. For a general description of gelatin and
`can optionally comprise from about 0.625% to about
`25% of a second pharmaceutical active, or mixtures
`gelatin-based capsules, see Remingtons's Pharmaceutical
`thereof.
`Sciences, 16th ed., Mack Publishing Company, Easton,
`65 Pa. (1980), page 1245 and pages 1576-1582; and U.S.
`Pat. No. 4,935,243, to Borkan et al., issued Jun. 19, 1990;
`these two references being incorporated herein by ref(cid:173)
`erence in their entirety.
`
`Soft Gelatin Capsules
`Preselected amounts of the highly concentrated liq(cid:173)
`uid pharmaceutical compositions of the present inven(cid:173)
`tion can also be encapsulated in a soft gelatin shell.
`Optionally, the soft gelatin shell is essentially transpar(cid:173)
`ent so as to enhance the aesthetic qualities of the cap(cid:173)
`sule. The soft gelatin shells comprise the following
`essential, as well as optional, components.
`
`Optional Components
`Other components which can be incorporated into
`the compositions of the instant invention include color-
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1012, Pg. 5 of 9
`
`

`

`5,141,961
`
`9
`The soft gelatin shell of the capsules of the instant
`invention, as initially prepared, comprises from about
`20% to about 60% gelatin, more preferably from about
`25%- to about 50% gelatin, and most preferably from
`about 40% to about 50% gelatin. The gelatin can be of
`Type A, Type B, or a mixture thereof with bloom num(cid:173)
`ber!> ranging from about 60 to about 300.
`
`10
`409-449; F. S. Hom et al., "Capsules. Soft" Encyclopedia
`of Pharmaceutical Technology. vol. 2, J. Swarbrick and J.
`C. Boylan, eds. (Marcel Dekker. Inc., New York, 1990)
`pp. 269-284; M. S. Patel et al., "Advances in Softgel
`5 Formulation Technology", Manufacturing Chemist,
`vol. 60, no. 7, pp. 26-28 (July 1989); M. S. Patel et al.,
`"Softgel Technology", Manufacturing Chemist, vol. 60,
`no. 8, pp. 47-49 (August 1989); R. F. Jimerson, "Softgel
`(Soft Gelatin capsule) Update", Drug Development and
`Industrial Pharmacy (lnterphex '86 Conference), vol. 12,
`no. 8 & 9, pp. 1 133-I 144 (1986); and W. R. Ebert, "Soft
`Elastic Gelatin capsules: A Unique Dosage Form",
`Pharmaceutical Technology, vol. 1, no. 5, pp. 44-50
`(1977); these references are incorporated by reference
`herein in their entirety. The resulting soft gelatin cap(cid:173)
`sule is soluble in water and in gastrointestinal fluids.
`Upon swallowing the capsule, the gelatin shell rapidly
`dissolves or ruptures in
`the gastrointestinal
`tract
`thereby introducing the pharmaceutical actives into the
`physiological system.
`
`Plasticizer
`A plasticizer is another essential component of the to
`soft gelatin shells of the instant invention. One or more
`