`Yu et al.
`
`[19]
`
`[75]
`
`[54] SOLVENT SYSTEM ENHANCING THE
`SOLUBILITY OF PHARMACEUTICALS FOR
`ENCAPSULATION
`Inventors: ManS. Yu, Rochester, N.Y.; Foo S.
`Hom, Safety Harbor; Sibaprasanna
`Chakrabarti, Oldsmer, both of Fla.;
`Chong-Heng Huang, Madison, N.J.;
`Mahendra Patel, Swindon, England
`[73] Assignee: R. P. Scherer Corp., Troy, Mich.
`The portion of the term of this patent
`[ *] Notice:
`subsequent to Dec. 10, 2008 has been
`disclaimed.
`[21] Appl. No.: 890,285
`May 26,1992
`[22] Filed:
`
`Related U.S. Application Data
`[63] Continuation of Ser. No. 642,187, Jan. 16, 1991, aban(cid:173)
`doned, which is a continuation of Ser. No. 104,911,
`Oct. 9, 1987, Pat. No. 5,071,643, which is a continua(cid:173)
`tion-in-part of Ser. No. 920,577, Oct. 17, 1986, aban(cid:173)
`doned.
`[51]
`Int. Cl.s ......................... A61K 9/08; A61K 9/48;
`A61K 9/20; A61K 47/34
`[52] u.s. Cl ..................................... 424/455; 424/456;
`424/465; 514/772.7
`[58] Field of Search ................... 424/80, 78, 455, 456;
`514/772.7
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`3,557,280 1/1971 Weber et al .......................... 424/80
`3,849,549 11/1974 Dempski et al ................ 514/420 X
`3,851,051 11/1974 Miske! et al ..
`4,002,718 1/1977 Gardella et al ..................... 424/455
`4,145,440 3/1979 Fitch et al ........................... 514/570
`4,472,376 9/1984 Kamishita ....................... 514/944 X
`4,486,412 12/1984 Shah et al ........................... 424/456
`4,525,348 6/1985 Arizono et al ........................ 424/81
`4,690,823 9/1987 Lohner et al ....................... 424/456
`4,701,327 10/1987 Henmi et al ........................ 424/455
`4,708,834 11/1987 Cohen et al ......................... 424/456
`4,713,246 12/1987 Begum et al ........................ 424/455
`4,798,725 1/1989 Patel .................................... 424/456
`
`111111111111111111111111111111111111111111111111111111111111111111111111111
`US005360615A
`5,360,615
`[11] Patent Number:
`[45] Date of Patent: * Nov. 1, 1994
`
`FOREIGN PATENT DOCUMENTS
`0086468 2/1982 European Pat. Off ..
`0070714 7/1982 European Pat. Off ............. 514/570
`2079600 1/1982 United Kingdom ................ 514/570
`2096890 10/1982 United Kingdom ................ 514/420
`W085/03439 8/1985 WIPO ................................. 514/629
`Primary Examiner-Edward J. Wehman
`Attorney, Agent, or Firm-Allegretti & Witcoff, Ltd.
`[57]
`ABSTRACT
`This invention relates to a solvent system for enhancing
`the solubility of an acidic, basic, or amphoteric pharma(cid:173)
`ceutical agent to produce a highly concentrated solu(cid:173)
`tion suitable for softgel filling or two piece encapsula(cid:173)
`tion. The solvent system comprises polyethylene glycol
`containing 0.2-1.0 mole equivalents of an ionizing agent
`per mole equivalent pharmaceutical agent and 1-20%
`water. Glycerin or polyvinylpyrrolidone may be added
`to further enhance the solubility of certain drugs. The
`disclosed solvent system is capable of enhancing solubil(cid:173)
`ities of pharmaceutical agents 40-400%.
`The ionizing agent functions by causing partial ioniza(cid:173)
`tion (neutralization) of the free pharmaceutical agent.
`When the pharmaceutical agent is acidic, the ionizing
`agent is preferably a hydroxide ion species, whereas
`when the pharmaceutical agent is basic, the ionizing
`agent is preferably a hydrogen ion species. For ampho(cid:173)
`teric pharmaceutical agents, either hydroxide ion or
`hydrogen ion sources may be utilized to effect partial
`ionization.
`The disclosed solvent system is useful because it not
`only provides for the enhancement or improvement of
`bioavailability of acidic, basic and amphoteric pharma(cid:173)
`ceutical agents by delivering them already in solution,
`but it also provides for a highly concentrated solution
`capable of encapsulation in a small enough vessel to
`permit easy swallowing.
`The highly concentrated solid solutions of the present
`invention are also useful for conversion into tablets and
`as veterinary spot and pour on preparations.
`
`19 Claims, No Drawings
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1014, Pg. 1 of 10
`
`
`
`SOLVENT SYSTEM ENHANCING THE
`SOLUBILITY OF PHARMACEUTICALS FOR
`ENCAPSULATION
`
`This application is a continuation of application Ser.
`No. 07/642,187, filed Jan. 16, 1991, abandoned, which is
`a continuation of application Ser. No. 07/104,911, ftled
`Oct. 9, 1987, now U.S. Pat. No. 5,071,643, which is a
`continuation-in-part of application Ser. No. 06/920,577,
`filed Oct. 17, 1986, abandoned.
`
`BACKGROUND OF THE INVENTION
`1. Field of the Invention
`This invention relates to a novel solvent system for 15
`enhancing the solubility of pharmaceutical agents by
`partial ionization to produce highly concentrated pri(cid:173)
`marily non-aqueous water miscible solutions of those
`agents; which as liquids are suitable for encapsulation in
`both softgels (previously known as soft elastic gelatin 20
`capsules) and in two piece hard gelatin shells, which can
`be sealed to retain liquid; which as semi-solids are suit(cid:173)
`able for encapsulation in two-piece hardshell capsules;
`and which as solid solutions are suitable for conversion
`into tablets. The solvent system of the present invention 2
`5
`is useful in that it provides for the encapsulation of a
`pharmaceutical agent in a volume of solution that is
`small enough to permit easy swallowing. It further
`provides for the preparation of highly concentrated 30
`solutions of a pharmaceutical agent having utility for
`pour on and spot on preparations in veterinary medi(cid:173)
`cine.
`Filled one-piece softgels have been widely known
`and used for many years and for a variety of purposes. 35
`Because softgels have properties which are quite differ(cid:173)
`ent from telescoping two-piece hardshell capsules, the
`softgels are capable of retaining a liquid fill material.
`The fill material may vary from industrial adhesives to
`bath oils. More commonly, the softgels are used to 40
`enclose or contain consumable materials such as vita(cid:173)
`mins and pharmaceuticals in a liquid vehicle or carrier.
`Generally, not all liquids are suitable as vehicles or
`carriers for enclosing softgels. For example, water,
`propylene glycol, glycerin and low molecular alcohols, 45
`ketones, acids, amines and esters cannot be filled in
`softgels by themselves and can only be present in small
`amounts. In particular, concentrations of water greater
`than 20% will dissolve the gelatin shell. Liquids that are
`suitable for ftlling softgels vary from water immiscible so
`liquids such as vegetable oils, aromatic oils, aromatic
`and aliphatic hydrocarbons, chlorinated hydrocarbons,
`ethers and esters, to water miscible nonvolatile liquids,
`such as polyethylene glycols and nonionic surfactants.
`There are specified limitations to the use of certain 55
`liquids as fill vehicles for softgels. For example, the pH
`of the fill liquid should not be below 2.5 or above 7.5. At
`pH's below 2.5, the gelatin is hydrolyzed causing leak(cid:173)
`ing, whereas at pH's greater than 7.5, the gelatin is
`tanned resulting in decreased solubility of the gelatin 60
`shell. Moreover, emulsions of oil/water or water/oil
`are not suitable for softgel encapsulation because they
`eventually break up releasing water which dissolves the
`gelatin shell.
`Vitamins and pharmaceuticals that naturally occur as 65
`liquids are ideally suited for softgels. These naturally
`occurring liquids are simply mixed with a miscible liq(cid:173)
`uid carrier which is also suited as a softgel ftll.
`
`1
`
`5,360,615
`
`2
`Vitamins and pharmaceuticals that naturally occur as
`solids may be ftlled into softgels in liquid form under
`primarily one of two approaches-either as a suspen(cid:173)
`sion of the solid in a liquid carrier or as a solution of the
`5 pharmaceutical agent in the appropriate solvent. Each
`approach has its attendant problems. For example, in
`the suspension, the solids must have a particle size no
`greater than 80 mesh. Coarser materials prevent the
`softgel filling equipment from functioning properly.
`10 They also prevent the achievement of a good "content
`uniformity" throughout the batch.
`By contrast, a solution provides the best liquid form
`to obtain optimal "content uniformity" in a batch. In
`addition, a solution provides a faster and more uniform
`absorption of a pharmaceutical agent than does a sus(cid:173)
`pension. Because of these distinct technical advantages,
`the solution is preferred over the suspension.
`However, a problem in the art is that an appropriate
`solution of the pharmaceutical agent cannot always be
`achieved. One constraint is size. Often, it is not possible
`to dissolve the pharmaceutical agent in a volume of
`solvent small enough to produce a softgel that is appro(cid:173)
`priate from the standpoint of economics and patient
`acceptance. Another constraint, is the solvent itself.
`The solvent must have sufficient solvating power to
`dissolve a large amount of the pharmaceutical agent to
`produce a highly concentrated solution, and yet not
`hydrolyze, dissolve, or tan the softgel.
`It is a primary object of the present invention to pro(cid:173)
`vide a solvent system which is capable of producing
`highly concentrated solutions of pharmaceutical agents
`and that these highly concentrated solutions be suitable
`for filling into softgels.
`Like the one-piece softgels, the two-piece telescoping
`hardshell capsules have also been used for many years
`and for a variety of purposes. Unlike the one-piece
`softgels, the two piece capsules are not a sealed system
`and hence are generally not suited for handling liquids.
`However, a two-piece capsule can handle a liquid with(cid:173)
`out leaking provided that it is properly sealed or that
`the liquid is converted into a solution which is either
`solid or semi-solid at room temperature. If the solid or
`semi-solid solution contained within the two-piece cap(cid:173)
`sule is a highly concentrated solution of a pharmaceuti(cid:173)
`cal agent, then the advantages possessed by a solution
`over a suspension are made available to both the user
`and the manufacturer. Specifically, the advantage of a
`faster and more uniform absorption of the pharmaceuti(cid:173)
`cal agent is available to the user of the two-piece cap(cid:173)
`sule, while the advantage of uniformity of the batch is
`available to the capsule manufacturer.
`It is a further object of the present invention to pro-
`vide a solvent system that is capable of producing
`highly concentrated solutions of pharmaceutical agents
`that are solid or semi-solid solutions at room tempera(cid:173)
`ture and that these solutions also be suitable for two-
`piece hardshell encapsulation. The highly concentrated
`solutions that are solid at room temperature have the
`additional utility of being suitable for conversion into
`tablets.
`Because most pharmaceutical agents are acidic, basic,
`or amphoteric in nature, it is a further object of this
`invention to provide a solvent system (pharmaceutical
`carrier system) which with minor modification could be
`equally useful for a pharmaceutical agent regardless of
`its basic, acidic, or amphoteric nature.
`Producing a highly concentrated solution of any
`acidic amphoteric or basic pharmaceutical agent is use-
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1014, Pg. 2 of 10
`
`
`
`5,360,615
`
`3
`ful because it permits the encapsulation of a unit dose of
`the pharmaceutical agent in a softgel or two-piece cap(cid:173)
`sule that is small enough to permit easy swallowing.
`Filling of a unit dose in a small softgel or 2-piece capsule
`to permit easy swallowing is useful because it increases 5
`patient acceptance of the medication. Patient accep(cid:173)
`tance is especially important in the case of prescription
`medications, because patient acceptance of the medica(cid:173)
`tion is a substantial step towards solving one of the
`major problems of prescription drug therapy-patient 10
`noncompliance with the prescribed regimen. A further
`utility of the disclosed solvent system is enhancement of
`bioavailability of the dissolved pharmaceutical agent.
`Enhanced bioavailability occurs as a result of delivering
`the pharmaceutical agent already in solution at the site 15
`of absorption, permitting a faster and more uniform
`absorption to occur.
`2. Description of Related Art
`Weber and Molenaar U.S. Pat. No. 3,557,280, teaches
`the preparation of aqueous solutions of oxytetracycline 20
`suitable for intramuscular and intravenous injection or
`for administration as a syrup in pediatric cases. The
`Weber and Molenaar (Weber) invention consists of
`dissolving oxytetracycline in water, in which a given
`quantity of polyvinylpyrrolidone has been dissolved, to 25
`which has been added a suitable quantity of magnesium
`salt, the pH of which has been adjusted to between
`8.0-9.5 using a base such as sodium hydroxide, ammo(cid:173)
`nia, etc.
`Although Weber uses polyvinylpyrrolidone to en- 30
`hance the solubility of oxytetracycline in an aqueous
`system, Weber neither teaches nor suggests that polyvi(cid:173)
`nylpyrrolidone would also be useful for enhancing solu(cid:173)
`bility of other pharmaceutical agents in non-aqueous
`systems. Moreover, the aqueous solutions taught by 35
`Weber are totally unsuited for either softgel or two(cid:173)
`piece encapsulation, since such aqueous solutions would
`dissolve the gelatin shells.
`The present invention differs from Weber in anum(cid:173)
`ber of other respects as well. Whereas Weber teaches 4D
`the formation of relatively dilute solutions (1-20%), the
`present invention teaches the preparation of more
`highly concentrated solutions (30-80%) requiring more
`skill than that disclosed in Weber.
`Whereas Weber teaches at column 3, line 25 that a 45
`salt suitable for chelating, such as magnesium, is "essen(cid:173)
`tial" to enhance the solubility of oxytetracycline, the
`present invention teaches the preparation of highly
`concentrated non-aqueous solutions of pharmaceutical
`agents without resorting to chelate formation to en- 50
`hance solubility.
`Although both Weber and the present invention use
`the base, sodium hydroxide, in the preparation of their
`pharmaceutical formulations, the role played by the
`sodium hydroxide in each invention differs. Whereas 55
`Weber uses the sodium hydroxide to adjust the pH to
`between 8.0-9.5 as to increase the shelf life of the oxy(cid:173)
`tetracycline solution (see Merck Index, 9th edition at p.
`904), the present invention uses the sodium hydroxide to
`enhance the solubility of an acidic pharmaceutical agent 60
`by forming as much of the ionized form of the acidic
`agent as is capable of being solvated by the system.
`Gardella et al, U.S. Pat. No. 4,002,718, teaches at
`column 3, line 47, the use of small amounts of polyvinyl(cid:173)
`pyrrolidone or glycerin to hasten dissolution of micron- 65
`ized digoxin in a liquid vehicle, polyethylene glycol, to
`form a solution suitable for softgels. Unlike Gardella,
`which only teaches the use of polyvinylpyrrolidone or
`
`4
`glycerin as a formulatory agent to hasten or speed up
`dissolution, the present invention teaches the use of
`glycerin or polyvinylpyrrolidone to enhance or in(cid:173)
`crease the amount of the pharmaceutical agent that is
`soluble in a given volume of liquid.
`In further contrast, Gardella only teaches the produc(cid:173)
`tion of very dilute solutions (0.1%) for encapsulation,
`whereas the present invention teaches the production of
`highly concentrated solutions (30-80% ). Because the
`solutions of the present invention are 300-800 times
`more concentrated than that taught by Gardella, the
`teachings of Gardella are not applicable to the present
`invention. Moreover, Gardella does not even suggest
`that glycerin, propylene glycol, or polyvinylpyrroli(cid:173)
`done would be useful for enhancing solubilities of phar(cid:173)
`maceutical agents as to produce 30-80% solutions of
`those agents.
`Wagner, U.S. Pat. No. 4,562,192, suggests the use of
`polyvinylpyrrolidone as a formulatory agent (adjuvant)
`for pharmaceutical preparations. However, Wagner
`neither teaches nor suggests that polyvinylpyrrolidone
`is useful for enhancing the solubility of a pharmaceuti(cid:173)
`cal agent in a given volume of liquid.
`
`SUMMARY OF THE INVENTION
`The present invention generally relates to a pharma(cid:173)
`ceutical carrier system ("solvent system") for enhanc(cid:173)
`ing the solubility of any acidic, basic, or amphoteric
`pharmaceutical agent by partial ionization to produce a
`highly concentrated primarily non-aqueous solution
`suitable for filling softgels or for two piece encapsula(cid:173)
`tion or for tablet formation, the solvent system compris(cid:173)
`ing in its simplest form 10-80% by weight polyethylene
`glycol, a solubility enhancing amount of either hydrox(cid:173)
`ide or hydrogen ion and 1-20% by weight of water.
`In particular, the present invention relates to a sol(cid:173)
`vent system for enhancing the solubility of an acidic
`pharmaceutical agent to produce a highly concentrated
`solution suitable for softgel filling comprising 10-80%
`polyethylene glycol, a solubility enhancing amount of
`hydroxide ion, preferably 0.2-1.0 mole equivalents of
`hydroxide ion per mole equivalent of acid in an acidic
`pharmaceutical agent, and 1-20% by weight of water.
`In addition, the present invention also relates to a
`simple modification of the disclosed solvent system
`wherein hydrogen ion is substituted for hydroxide ion,
`thereby enhancing the solubility of any basic pharma(cid:173)
`ceutical agent in polyethylene glycol so as to produce a
`highly concentrated solution of the basic pharmaceuti(cid:173)
`cal agent which is also suited for softgel filling, encapsu(cid:173)
`lation or tablet formation.
`The polyethylene glycol used herein has an average
`molecular weight of between about 200-100,000 daltons
`(hereinafter, all molecular weights are expressed in
`daltons). Moreover, the weight of polyethylene glycol
`selected affects the type of solution produced. Polyeth(cid:173)
`ylene glycol having an average molecular weight from
`about 200-800, preferably from about 400-700, and
`most preferably about 600, produces a softgel fill solu(cid:173)
`tion that is a liquid. Polyethylene glycol having an aver(cid:173)
`age molecular weight from about 800-10,000, prefera(cid:173)
`bly from about 2,000-8,000, produces a softgel fill solu(cid:173)
`tion that is semi-solid, and polyethylene glycol having
`an
`average molecular weight between
`about
`10,000-100,000, preferably about 15,000-60,000, pro(cid:173)
`duces a softgel fill solution that is solid.
`Contemplated equivalents of polyethylene glycol
`include analogs, such as the polyethylene glycol ethers
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1014, Pg. 3 of 10
`
`
`
`5,360,615
`
`6
`This invention further relates to a modification of the
`disclosed system wherein the ionizable species of the
`pharmaceutical agent of interest is added directly to
`polyethylene glycol systems in the form of its pharma(cid:173)
`ceutically acceptable salt. By selecting the proper ratio
`of the free pharmaceutical agent and its salt, the solubil(cid:173)
`ity of that agent can be maximized.
`
`20
`
`10
`
`DETAILED DESCRIPTION
`The invention encompasses a solvent system for pre-
`paring highly concentrated solutions of pharmaceutical
`agents wherein the prepared solutions are particularly
`suitable for softgel filling. The pharmaceutical agents
`suitable for use with the solvent system of this invention
`15 are either acidic, basic or amphoteric compounds, i.e.,
`compounds that are readily ionizable.
`Specific examples employing the disclosed solvent
`system are given for four acidic pharmaceutical agents,
`indomethacin, ibuprofen, naproxen and acetaminophen.
`By varying the acidic pharmaceutical agent and by
`employing the solvent system taught in this invention,
`one of ordinary skill in the art could produce a highly
`concentrated solution of any acidic pharmaceutical
`agent and said concentrated solution would be suitable
`for fllling into softgels.
`The present solvent system uses polyethylene glycol
`(PEG) as its base, preferably having an average molecu(cid:173)
`lar weight between about 200-100,000, and most prefer(cid:173)
`ably having an average molecular weight between
`about 400-600 for liquid fills, between about 800-10,000
`for semi-solid fills, and between 10,000-100,000 for solid
`fills. Non-ionized acidic pharmaceutical agents have
`some solubility in polyethylene glycol, utilizing the
`solvents hydrophobic binding sites. However, this solu(cid:173)
`bility alone is insufficient to produce a highly concen(cid:173)
`trated solution which would permit encapsulation of a
`unit dose in a softgel that would be small enough to
`permit easy swallowing. For example, Table 1 lists
`solubilities of the acidic pharmaceutical agents, ibu(cid:173)
`profen, naproxen, indomethacin and acetaminophen in
`polyethylene glycol and the corresponding minimum
`softgel capsule size required to encapsulate a unit dose
`as a clear solution. Table 1 further lists the enhanced
`solubilites of the same pharmaceutical agents in the
`disclosed solvent system and the corresponding re(cid:173)
`duced softgel size. In the disclosed solvent system, the
`enhancement in solubility is presumably due in part to
`the further ability of the solvent, polyethylene glycol, to
`utilize separate hydrophilic binding sites to solvate the
`ionized (hydrophilic) species of the pharmaceutical
`agent.
`
`TABLE 1
`SOLUBILITIES AND CAPSULE SIZE FOR UNIT DOSES
`OF SOME ACIDIC PHARMACEUTICAL AGENTS IN
`POLYETHYLENE GLYCOL AND IN THE DISCLOSED
`SOL VENT SYSTEM
`Using Polyethylene
`Gl::z:col600
`Solu- Minimum
`Unit
`Dosage bility Capsule
`(%)
`(mg)
`Size*
`
`Using the Disclosed
`Solvent S::z:stem
`Minimum
`Solubility Capsule
`(%)
`Size
`
`Agent
`
`~=--~~:__~~--==---~~-..:.:::... __
`
`5
`of various alcohols including but not limited to tetra(cid:173)
`glycol-the polyethylene glycol ether oftetrahydrofur(cid:173)
`furyl alcohol, and copolymers of polyethylene glycol.
`Further enhancement of the solubility of the pharma(cid:173)
`ceutical agent in polyethylene glycol is accomplished 5
`by the addition of 4-12% by weight of glycerin or
`propylene glycol and/or by the further addition of
`1-20% by weight of polyvinylpyrrolidone, said polyvi(cid:173)
`nylpyrrolidone preferably having an average molecular
`weight between about 10,000-100,000.
`For the acidic pharmaceutical agents, it is preferred
`that the concentration of liquids with hydroxyl ions,
`such as glycerin, ethanol, propylene glycol be kept as
`low as possible. In contrast, the concentration of water
`in the solvent system should be as high as possible.
`The present invention further relates to highly con(cid:173)
`centrated solutions of the acidic pharmaceutical agents
`ibuprofen, naproxen, indomethacin, and acetaminophen
`suitable for filling softgels or two piece capsules, or for
`tablet formation;
`said solution of ibuprofen comprising 40-80% by
`weight ibuprofen, 0.1-1.5 moles of hydroxide ion
`per mole of ibuprofen, 1-20% by weight water,
`and 4-12% by weight glycerin or propylene glycol
`in polyethylene glycol, wherein said hydroxide ion 25
`is more preferredly in the range of0.2-0.5 moles of
`hydroxide ion per mole of ibuprofen;
`said solution of naproxen comprising 20-50% by
`weight naproxen, 0.2-0.9 moles of hydroxide ion
`per mole ofnaproxen and 1-20% by weight water 30
`in polyethylene glycol, wherein said hydroxide ion
`is more preferredly in the range of 0.4-0.6 moles of
`hydroxide ion per mole of naproxen;
`said solution of indomethacin comprising 30-60% by
`weight indomethacin, 0.5-1.0 moles of hydroxide 35
`ion per mole of indomethacin, and 1-20% by
`weight water in polyethylene glycol; and
`said solution of acetaminophen comprising 25-40%
`by weight acetaminophen, 0.4-1.0 moles of hy(cid:173)
`droxide ion per mole of acetaminophen, and 40
`1-20% by weight water in polyethylene glycol.
`The solubility of the above mentioned acidic pharma(cid:173)
`ceutical agents in said solutions is further enhanced
`2-10% by the further addition of 3-10% by weight of
`glycerin, or propylene glycol or 1-20% by weight of 45
`polyvinylpyrrolidone; the higher percentages (>5%)
`of polyvinylpyrrolidone being more suited for use in
`suppositories, two piece capsules, and tablet formation.
`The present invention also relates to unit dose forms
`of ibuprofen, naproxen, indomethacin, and acetamino- 50
`phen comprising either a softgel or two piece capsule or
`a tablet containing within a therapeutically effective
`amount of the appropriate highly concentrated solution
`of said pharmaceutical agent as disclosed above.
`Exactly as was disclosed for the acidic pharmaceuti- 55
`cal agents, selection of the polyethylene glycol solvent
`in the disclosed molecular weight ranges enables the
`production ofliquid semi-solid and solid solutions of the
`basic pharmaceutical. agents.
`By way of example, said basic pharmaceutical agents 60
`include but are not limited to cimetidine, ranitidine, and
`nifedipine.
`Finally, the present invention relates to a solvent
`system for enhancing the solubility of amphoteric phar(cid:173)
`maceutical agents wherein either hydrogen or hydrox- 65
`ide ions can be used to enhance the solubility of the
`amphoteric agent by partially ionizing it in the polyeth(cid:173)
`ylene glycol systems just described.
`
`200
`250
`25
`
`23
`15
`25
`
`14 oblong
`20 oblong
`I round
`
`67
`40
`35
`
`5 oblong
`7 oblong
`I round
`
`Ibuprofen
`Naproxen
`lndometha-
`cin
`Acetamino-
`ph en
`*minimum capsule size for a clear fill as a solution and not as a suspension.
`
`500
`
`25
`
`30 oval
`
`35
`
`20 oval
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1014, Pg. 4 of 10
`
`
`
`5,360,615
`
`8
`mole equivalent of about 0.3 (0.3 moles of sodium hy(cid:173)
`droxide/mole of the monoacid compound ibuprofen).
`TABLE 3
`EFFECT OF SODIUM HYDROXIDE ON THE
`SOLUBILITY OF IBUPROFEN IN PEG 400
`Sodium
`Polyethylene
`Glycol400 Hydroxide Water Appearance
`(mg)
`(wt %) (Room temp)
`(MIE)
`
`Ibuprofen
`(mg)
`
`0.1
`
`1.5
`
`200
`
`200
`
`Insoluble (slight
`ppt)
`200
`Soluble
`2.8
`0.2
`200
`Soluble
`4.1
`0.3
`200
`200
`Soluble
`5.2
`0.4
`200
`200
`Insoluble (solid
`0.5
`6.6
`200
`200
`admixture)
`- - - - - - - - - - - - - - - - - - - . . . : . . . - -
`
`15
`
`7
`Thus, the present solvent system enhances the solu(cid:173)
`bility of acidic pharmaceutical agents in polyethylene
`glycol by increasing the number of species of the acidic
`agent (ionized and unionized) that are available to go
`into solution and by providing adequate solvation for 5
`each species. The present solvent system accomplishes
`this increase in solubility by utilizing both the hydro(cid:173)
`phobic and hydrophilic binding sites in polyethylene
`glycol; and by further employing a combination of ad(cid:173)
`junctive devices which act complementary to one an- 10
`other producing an overall solubility that is greater than
`could be produced by the addition of any one alone.
`The adjunctive devices employed in the present inven-
`tion include hydroxide ion, water, glycerin, and/or
`polyvinylpyrrolidone.
`In the present solvent system in its simplest form
`comprising polyethylene glycol, sodium hydroxide, and
`water, the polyethylene glycol acts to dissolve the free
`form of the acidic agent in monomer, dimer, trimer, etc. 20
`form; the sodium hydroxide is present in sufficient quan(cid:173)
`tity to only partially form the sodium salt of the acidic
`pharmaceutical agent; and the small amount of water
`present acts to form a solvation sphere around the acid
`salt permitting it to go into solution in the polyethylene 25
`glycol.
`Table 2 shows the cumulative effect of the addition of
`several of the adjunctive devices on the solubility of
`ibuprofen in PEG 600-polyethylene glycol having an
`average molecular weight of 600. As Table 2 suggests, 30
`the combination of hydroxide ion and water in PEG 600
`produces a 67% solution of ibuprofen versus a 23%
`solution for PEG 600 without adjuncts. This is a 44%
`overall enhancement in solubility produced by the pres(cid:173)
`ent solvent system.
`A similar result is found for the other three acidic
`pharmaceutical agents tested in this experiment and
`there is no reason to believe that the combination of
`hydroxide ion and water would not produce an analo(cid:173)
`gous enhancement of solubility in PEG for other acidic 40
`pharmaceutical agents not tested in this invention.
`TABLE2
`EFFECT OF ADJUNCTIVE DEVICES ON THE
`SOLUBILITY OF IBUPROFEN IN PEG 600
`Ibuprofen
`Ibuprofen PEG 600 Glycerin Water M/E
`(mg)
`(mg)
`(wt %) OH•
`Solubility
`(wt %)
`
`An unexpected result was obtained when potassium
`hydroxide was substituted for sodium hydroxide in the
`preceding discussion. At equimolar concentrations of
`hydroxide ion, the solubility of ibuprofen, naproxen,
`indomethacin and acetaminophen was greater in the
`presence of potassium hydroxide than in the presence of
`sodium hydroxide. Moreover, much greater concentra(cid:173)
`tions of potassium hydroxide than sodium hydroxide
`could be utilized to prepare the highly concentrated
`solutions of the acidic pharmaceutical agents in polyeth-
`ylene glycol without precipitation occurring. For exam(cid:173)
`ple, in the case of ibuprofen in PEG 400, precipitation
`occurs in the presence of 0.5 or more mole equivalents
`of sodium hydroxide, whereas no precipitation occurs
`in the presence of 1.0 mole equivalents of potassium
`hydroxide even at 4o C. (Table 4). Accordingly, potas(cid:173)
`sium hydroxide is the preferred form of hydroxide ion
`not only because it enhances the solubility of an acidic
`35 pharmaceutical agent to a greater extent than sodium
`hydroxide but also because it is less likely to result in
`precipitation over a wide variety of concentration
`ranges even at low temperatures (4° C.) as may occur
`during shipping.
`The above result is very likely explainable based upon
`the relative sizes of the sodium and potassium ions. The
`potassium ion is larger than the sodium ion. Hence, the
`charge on the potassium ion is dispensed over a larger
`area causing it to require less solvation thereby permit-
`45 ting more solvation for other species. Accordingly, any
`hydroxide species, with a pharmaceutically acceptable
`cation as large or larger than potassium, such as ammo(cid:173)
`nium and the like, should be equally or more suited to
`producing a highly concentrated solution of an acidic
`pharmaceutical agent.
`If one wishes to further enhance solubility an addi(cid:173)
`tional 2-10% beyond that produced by the polyethyl(cid:173)
`ene glycol, hydroxide ion, and water system, it is neces(cid:173)
`sary to either add glycerin and propylene glycol or
`polyvinylpyrrolidone or both to the disclosed system.
`Glycerin is especially effective in enhancing the solubil-
`ity of ibuprofen when present in a preferred concentra(cid:173)
`tion range of 3-12% by weight. The concentration
`range most preferred being 4-8% by weight.
`Polyvinylpyrrolidone enhances the solubility of
`acidic pharmaceutical agents when present in the dis(cid:173)
`closed system in a concentration range of 1-20%. The
`preferred average molecular weight for the polyvinyl(cid:173)
`pyrrolidone is 10,000-100,000. The addition of polyvi(cid:173)
`nylpyrrolidone to the present system can serve a dual
`function. Not only does the polyvinylpyrrolidone en-
`hance solubility as to enable production of a highly
`concentrated solution suitable for filling softgels, but it
`
`0
`0
`870
`200
`0
`0.3
`4.5
`0
`100
`200
`0.3
`3.3
`402
`6.4
`100
`*M/E = moles of hydroxide ion for each mole of acidic drug.
`
`23%
`61%
`67%
`
`50
`
`The addition of sodium hydroxide and water to ibu(cid:173)
`profen (Table 3), or to naproxen, indomethacin, or acet(cid:173)
`aminophen in polyethylene glycol (PEG) increases the 55
`solubility of that pharmaceutical agent up to a certain
`point. The further addition of sodium hydroxide beyond
`this point has the reverse effect and causes the pharma(cid:173)
`ceutical agent to precipitate out of solution as the so(cid:173)
`dium salt. The optimal amount of sodium hydrox- 60
`ide-the amount of sodium hydroxide producing maxi(cid:173)
`mum solubility of the acidic pharmaceutical agent in
`polyethylene glycol-was in all cases tested less than 1
`mole of sodium hydroxide for each mole of acid in the
`acidic drug, i.e., the NaOH concentration was always 65
`less than 1 mole equivalent. In the specific case of ibu(cid:173)
`profen in PEG 400 (Table 3), the solubility was maximal
`(47%) when the sodium hydroxide wa