111111
`
`1111111111111111111111111111111111111111111111111111111111111111111111111111
`US 20040157928Al
`
`(19) United States
`(12) Patent Application Publication
`Kim et al.
`
`(10) Pub. No.: US 2004/0157928 A1
`Aug. 12, 2004
`( 43) Pub. Date:
`
`(54) SOLVENT SYSTEM OF HARDLY SOLUBLE
`DRUG WITH IMPROVED DISSOLUTION
`RATE
`
`(76)
`
`Inventors: Jae-Hwan Kim, Seoul (KR);
`Kyung-Sik Lee, Suwon-shi (KR);
`Woo-Chou) Shin, Suwon-shi (KR);
`So-Ra Lee, Seoul (KR); Jae-Hun Yi,
`Suwon-shi (KR)
`
`Correspondence Address:
`SMITH PATENT OFFICE
`1901 PENNSYLVANIAAVENUE N W
`SUITE 200
`WASHINGTON, DC 20006
`
`(21) Appl. No.:
`
`10/682,989
`
`(22) Filed:
`
`Oct. 14, 2003
`
`(30)
`
`Foreign Application Priority Data
`
`Feb. 12, 2003
`Feb. 21, 2003
`
`(KR) ............................ 10-2003-0008931
`(KR) ............................ 10-2003-0011056
`
`Sep. 1, 2003
`
`(KR) ............................ 10-2003-0060665
`
`Publication Classification
`
`Int. CI? .................................................. A61K 31/192
`(51)
`(52) U.S. Cl. .............................................................. 514/570
`
`(57)
`
`ABSTRACT
`
`The present invention relates to a solvent system with
`improved disintegration degree and dissolution ratio of a
`hardly soluble drug by highly concentrating the drug
`through partial ionization, and by establishing optimal con(cid:173)
`ditions for enhancing bioavailability of the drug, such as the
`co-relation between the acid drug and the accompanied
`components, ionization degree of a solvent system, use of an
`appropriate cation acceptance, water content, selection of
`optimal mixing ratio of the respective components and use
`of specific surfactants, and to a pharmaceutical preparation
`comprising the same. The solvent system of the invention
`has advantages in that it can enhance bioavailability by
`improving the disintegration degree and dissolution ratio of
`a hardly soluble drug and also provide a capsule with a
`sufficiently small volume to permit easy swallowing.
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1010, Pg. 1 of 17
`
`

`

`Patent Application Publication Aug. 12, 2004 Sheet 1 of 4
`
`US 2004/0157928 A1
`
`Fig. 1
`
`Fig . .2
`
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`Relative dissolution test(water)
`
`c6ntrol
`example
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`Tirne(minute)
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1010, Pg. 2 of 17
`
`

`

`Patent Application Publication Aug. 12, 2004 Sheet 2 of 4
`
`US 2004/0157928 A1
`
`Fig. 3
`
`dissolution graph at PH 7.4
`
`5 100
`.......
`=:J
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`45
`
`t i me(m in.)
`
`dissolution data (PH 1 .2)
`
`-+-control
`--11-- examp I e
`
`190 soo
`5
`dissolution time(min.)
`
`dissolution ratio data(PH 4.0)
`dissolution ratio(%)
`40
`
`-+--control
`-a- example
`
`20
`
`0
`
`s
`
`60
`180
`time(min.)
`
`soo
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1010, Pg. 3 of 17
`
`

`

`Patent Application Publication Aug. 12, 2004 Sheet 3 of 4
`
`US 2004/0157928 A1
`
`Fig. 6
`
`dissolution ratio data(PH 6.8) ·
`dissolution ratio(~)
`120
`80
`40
`0
`
`....._control
`~ exarm:>le
`
`180 300 time (min.)
`
`Fig. 7
`
`,......,
`~ ........-
`0
`....... 90
`(tl
`'-
`8 60
`+' ;:::, 30
`-0
`(/) 0
`·--o
`
`(/)
`
`f Fig. 8
`
`!
`
`•.·
`
`dissolution ratio data (water)
`
`-+- control
`. ..-:.- examp I e
`
`5
`
`60
`time(min.)
`
`180
`
`300
`
`.
`relative dissolution test(water)
`
`'
`
`,......,
`~ ...._,
`o.
`:;:; 1~<0
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`5 00
`.....,
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`tac• : 10 :.~tJ ::: o l)O¢ ~no eoo
`time (min.)
`
`(/)
`(/)
`-o
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1010, Pg. 4 of 17
`
`

`

`Patent Application Publication Aug. 12, 2004 Sheet 4 of 4
`
`US 2004/0157928 A1
`
`Fig. 9
`
`-4-.J
`
`Jl')
`
`relative dissolution ratio(%)
`
`example
`control
`
`(l
`
`10
`
`..)j
`
`·1s
`time(min.)
`
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`~ t;\j
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`
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`
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`
`Fig. 10
`
`relative dissolution test(%)
`
`,-...
`~
`0 40
`in 30
`'-
`5 20
`~ 10
`g 0
`~ 0 10 20 30 40 50 60 ?0 80 90 100110 120
`time (min.)
`.
`
`....,.._ examp 1 e
`.:..a- control
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1010, Pg. 5 of 17
`
`

`

`US 2004/0157928 A1
`
`Aug. 12, 2004
`
`1
`
`SOLVENT SYSTEM OF HARDLY SOLUBLE DRUG
`WITH IMPROVED DISSOLUTION RATE
`
`BACKGROUND OF THE INVENTION
`[0001] 1. Field of the Invention
`
`[0002] The present invention relates to a solvent system
`with improved disintegration degree and dissolution ratio of
`a hardly soluble drug by highly concentrating the drug
`through partial ionization, and by establishing optimal con(cid:173)
`ditions for enhancing bioavailability of the drug, such as the
`co-relation between the acid drug and the accompanied
`components, ionization degree of a solvent system, use of an
`appropriate cation acceptance, water content, selection of
`optimal mixing ratio of the respective components and use
`of specific surfactants, and to a pharmaceutical preparation
`comprising the same.
`
`[0003] 2. Background of the Related Art
`
`In general, not all liquids are suitable as a vehicle
`[0004]
`or carrier for the filling material encapsulated in a soft
`capsule. For example, liquid is an indispensable part for the
`filling material of a capsule. However, water miscible liquids
`and volatile liquids cannot be contained as one of major
`components of the capsule filling materials since they can be
`migrated to the hydrophilic gelatin shell or penetrated
`through the gelatin shell to be volatilized. Such examples
`include water, alcohols, as well as emulsions. Similarly,
`gelatin plasticizers such as glycerin and propylene glycol
`cannot be a major component of the capsule filling material
`since the gelatin shell is highly susceptible of heat and
`humidity. However, water and alcohols can be used as a
`subsidiary component(less than about 5% of the capsule
`filling material), for example, a dissolution aid upon prepa(cid:173)
`ration of the capsule filling solution. Also, glycerin or
`propylene glycol in an amount of less than 10% can be used
`as a co-solvent, along with a liquid such as polyethylene
`glycol to cure the shell. Liquids which are widely used in the
`preparation determination include oil phases such as veg(cid:173)
`etable oils, mineral oils, non-ionic surfactants, polyethylene
`glycol ( 400, 600) and the like, which can be used alone or
`in combination.
`
`[0005] All the liquids, solutions, suspensions for prepara(cid:173)
`tion of capsules should be homologues and free-bubbles,
`and can flow by themselves at a temperature not exceeding
`35° C. This is because the adhesion temperature of the
`gelatin shell is 37 to 40° C. Also, the preparation to be
`formulated has a pH of 2.0 to 8.0. If the pH of the
`preparation is more acidic than the lower limit, hydrolysis
`may occur to weaken the gelatin shell, causing leakage. If
`the filling material is basic, the gelatin shell is tanned to
`induce cross-linking in the gelatin shell, which delays the
`disintegration time of the soft capsule.
`
`[0006] Upon investigation of prior arts related to soft
`capsules, U.S. Pat. No. 3,557,280 (Jan. 19, 1971) discloses
`the preparation of aqueous solutions of oxytetracycline.
`Specifically, pH was adjusted to the range of 8.0 to 9.5 to
`increase the storage life span of a hardly soluble drug and
`magnesium hydroxide (Mg(OH) 2) is used to increase the
`solubility of the filling material. However, when a gelatin
`capsule is prepared according to this prescription, cross
`linkings may occur within the gelatin molecular, causing the
`capsule shell insoluble, which is not proper for the object of
`the present invention.
`
`[0007] Korean Patent Application No. 1997-9001 (Mar.
`17, 1997) disclosed a method for producing an Ibuprofen
`composition comprising Ibuprofen, polyvinylpyrrolidone
`and polyethylene glycol, in which combined surfactants
`(polyoxyethylene sorbitan fatty acid ester and polyoxy 40
`castor oil) are added to a solution heated to 40 to 50° C. This
`invention is similar to the present invention in that a com(cid:173)
`bination of surfactants is used to improve the dissolution rate
`and the bioavailability of Ibuprofen. However, problems of
`highly hardly soluble drugs such as Naproxen cannot be
`solved by the simple use of a surfactant.
`
`[0008] Also, an example of the conventional ionizable
`solvent system is disclosed in U.S. Pat. No. 5,071,643. The
`object of this invention is for increasing the solubility of a
`drug by partial ionization. The use of sodium hydroxide
`(NaOH) accords with the object of the present invention in
`one aspect. However, strictly speaking, this invention is
`limited to a step to dissolvate a hardly soluble drug in an
`ionizable pharmaceutical solvent system by depending on
`pH only and the system has problems of precipitation as time
`goes by. Also, it teaches the use of glycerin or polyvinylpyr(cid:173)
`rolidone (Povidon) to increase an amount of a drug capable
`of being dissolved in a given volume of a liquid. However,
`it aims only at increase of the solubility in a prescribed
`volume.
`
`[0009] Also, U.S. Pat. No. 4,002,718 discloses use of
`polyvinylpyrrolidone or glycerin in a small amount to hasten
`dissolution of micronized Digoxin in polyethylene glycol in
`the preparation of a solution suitable for a soft gel.
`
`[0010] According to the foregoing prior arts, it has been
`described that an extremely diluted solution (0.1 %) and
`glycerin, propylene glycol, or polyvinylpyrrolidone (Povi(cid:173)
`don) are used in the preparation of a highly concentrated
`solution for producing a capsule, but there is no description
`regarding the improvements of the disintegration and dis(cid:173)
`solution rate. Also, since the capsules prepared according to
`the prior arts has an extremely low dissolution rate or the
`preparation are too bulky, and thus the arts failed to realize
`products in a commercial level.
`
`SUMMARY OF THE INVENTION
`
`[0011] The present inventors have conducted researches
`and studies to seek a method for improving bioavailability of
`hardly soluble drugs, and as a results, discovered that the
`bioavailability of the drugs can significantly be improved by
`highly concentrating the drug through partial ionization, and
`by compositely establishing optimal conditions for enhanc(cid:173)
`ing bioavailability of the drug, such as the co-relation
`between the acid drug and the accompanied components,
`ionization degree of a solvent system, use of an appropriate
`cation acceptance, water content, selection of optimal mix(cid:173)
`ing ratio of the respective components and use of specific
`surfactants, and completed the present invention.
`
`[0012] Thus, it is a primary object of the present invention
`to provide a solvent system which can prepare a highly
`concentrated solution of a hardly soluble drug or acidic drug
`and it is another object of the present invention to provide
`preparations such as a soft capsule having the improved
`disintegration degree and dissolution rate improved while
`having the bioavailability increased by the highly concen(cid:173)
`trated dissolution.
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1010, Pg. 6 of 17
`
`

`

`US 2004/0157928 Al
`
`Aug. 12, 2004
`
`2
`
`[0013]
`It is yet another object of the present invention to
`provide a pharmaceutical formulation, for example, a soft
`capsule, two-piece capsule or tablet comprising the above
`solvent system.
`
`[0014] To achieve the above object, in an aspect of the
`present invention, there is provided a solvent system for a
`hardly soluble drug or an acidic drug having the improved
`disintegration and dissolution rates, whereby the effect of the
`drug, that is, the bioavailability which is the ultimate pur(cid:173)
`pose of a preparation, is improved, and a pharmaceutical
`preparation comprising the solvent system and a hardly
`soluble acidic drug.
`
`[0015] More particularly, the pharmaceutical preparation
`according to the present invention comprises a hardly
`soluble acidic drug and a solvent system therefor, in which
`the solvent system comprises a pharmaceutically acceptable
`cation acceptance for increasing the solubility of the drug by
`partially ionizing the drug so that the drug exists in two
`forms of a free acid and a cationic salt, polyethylene glycol,
`water and a surfactant to improve the dissolution rate.
`
`[0016]
`In a preferred embodiment according to the present
`invention, the solvent system comprises 10 to 90% by
`weight, preferably 10 to 80% by weight, more preferably 30
`to 70% by weight of polyethylene glycol, 0.1 to 50% by
`weight, preferably 0.2 to 40% by weight, more preferably
`0.2 to 30% by weight of a surfactant and 1 to 15% by weight,
`preferably 3 to 12% by weight, more preferably 4 to 9% by
`weight of water, and 0.1 to 2 mole equivalent of a cation
`acceptance with respect to the hardly soluble acidic drug.
`
`[0017] As an exemplary to help better understanding of
`the present invention, the solvent system simply comprises
`10 to 90% by weight of polyethylene glycol (more prefer(cid:173)
`ably, polyethylene glycol 600), 0.1 to 2 mole equivalent of
`a cation acceptance (more preferably KOH, NaOH) per mole
`equivalent of the hardly soluble acidic drug to increase the
`solubility of the hardly soluble acidic drug, 0.1 to 50% by
`weight of a vehicle selected from surfactants (more prefer(cid:173)
`ably, Polyoxy 40 hydrogenated castor oil)and 0.1 to 15% by
`weight of water.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0018] The above and other objects, features and advan(cid:173)
`tages of the present invention will be apparent from the
`following detailed description of the preferred embodiments
`of the invention in conjunction with the accompanying
`drawing, in which:
`
`[0019] FIG. 1 is a graph showing the relation between the
`dissociation and the ionization of a drug with carboxylic
`acid, in which the ionization was performed using 10%
`KOH solution at 105° C. for one week (Y: dissociation rate,
`X: ionization degree);
`
`[0020] FIG. 2 is a graph showing the dissolution rate of a
`prescription according to the present invention and a com(cid:173)
`parative prescription in water;
`
`[0021] FIG. 3 is a graph showing the dissolution rate of a
`prescription according to the present invention and a com(cid:173)
`parative prescription in a phosphate buffer(ph 7.4);
`
`[0022] FIG. 4 is a graph showing the dissolution rate of a
`prescription according to the present invention and a com(cid:173)
`parative prescription at pH 1.2;
`[0023] FIG. 5 is a graph showing the dissolution rate of a
`prescription according to the present invention and a com(cid:173)
`parative prescription at pH 4.0;
`[0024] FIG. 6 is a graph showing the dissolution rate of a
`prescription according to the present invention and a com(cid:173)
`parative prescription at pH 6.8;
`[0025] FIG. 7 is a graph showing the dissolution rate of a
`prescription according to the present invention and another
`comparative prescription in water;
`[0026] FIG. 8 is a graph showing the dissolution rate of a
`prescription according to the present invention and another
`comparative prescription in water;
`[0027] FIG. 9 is a graph showing the dissolution rate of
`the prescription according to the present invention and
`another comparative prescription at pH 6.8; and
`[0028] FIG. 10 is a graph showing the dissolution rate of
`the prescription according to the present invention and a
`comparative prescription at pH 1.2.
`
`DETAILED DESCRIPTION OF THE
`PREFERRED EMBODIMENT
`[0029] Hereinafter, the present invention is described in
`detail.
`[0030] The solvent system according to the present inven(cid:173)
`tion is anew one with the improved disintegration and
`dissolution rate by adding a specific surfactant or a cation
`acceptance to a highly concentrated capsule filling material,
`which does not cause the precipitation problem even after
`time goes by, and thus can be used to prepare a highly
`concentrated solution of a hardly soluble drug.
`[0031] The solvent system of the invention primarily
`increases the solubility of a hardly soluble drug capable of
`being partially ionized to form a highly concentrated solu(cid:173)
`tion and secondarily improves the disintegration and the
`dissolution rates. Therefore, even when a liquid filling
`material is encapsulated in a soft capsule, the solvent system
`can improve the disintegration and dissolution rates of the
`capsule filling material. Also, the solvent system is very
`useful in that it can effectively encapsulate a drug in a highly
`concentrated solution with a volume that is small enough to
`permit easy swallowing.
`[0032] The conventional approaches to improve the avail(cid:173)
`ability of hardly soluble drugs have widely been carried out
`depending on the selection of a surfactant type vehicle and
`in some cases, unexpectedly, significant results were
`observed even when well known components were applied.
`Some of the previously mentioned prior arts are the cases.
`However, hardly soluble drugs have different solubility
`according to their chemical properties and the simple selec(cid:173)
`tion of a certain surfactant cannot be generally applied to
`drugs with extremely
`low solubility
`(for example,
`Naproxen).
`[0033] The system according to the present invention is
`definitely distinguished from the conventional systems in
`that it can be generally applied to hardly soluble compounds
`with extremely low solubility. For example, Ibuprofen is
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1010, Pg. 7 of 17
`
`

`

`US 2004/0157928 Al
`
`Aug. 12, 2004
`
`3
`
`well soluble in ethanol, acetone, and chloroform but hardly
`soluble in water while Naproxen is well soluble in acetone,
`soluble in chloroform but hardly soluble in water. That is,
`Ibuprofen can be solvated and formulated using common
`vehicles in some cases because it is better soluble than
`Naproxen for many vehicles, and also has a low melting
`point. However, in case of drugs with an extremely low
`solubility such as Naproxen, it has been impossible to be
`effectively dissolved until the present invention.
`
`[0034] Therefore, the present invention employs a solvent
`system which is definitely distinguishable from the prior
`arts, which is accomplished by compositely considering
`various factors, including optimal conditions for enhancing
`bioavailability of the hardly soluble acidic drugs, that is, the
`relation between hardly soluble acidic drugs and each of
`accompanied components, ionization degree of the solvent
`system, use of an appropriate cationic acceptance, water
`content and selection of the optimal mixing ratio of the
`constituting components, and therefore any of prior arts does
`not teach the present invention in this point of view.
`
`[0035] The improvement of the bioavailability which is
`sought in the present invention can be accomplished when
`the ionization degree of the drug reaches in the range of 10%
`to 65%, more preferably 40 to 55%, most preferably about
`50% and the water content in the solvent system is less than
`15%, in addition to use of the specific surfactant(s).
`
`[0036] Moreover, by establishing the above-described
`conditions, the present invention has advantages in that it
`can provide further benefits in addition to the improvement
`of the disintegration rate and the dissolution rate of a highly
`concentrated solution; that is, surfactants with various
`advantageous properties can be used alone or in combina(cid:173)
`tion, a capsule shell can be produced without glycerin, and
`the products made by encapsulating a drug in a highly
`concentrated solution by using the solvent system of the
`present invention has a relatively small volume allowing
`easy swallowing, as compared to products made by encap(cid:173)
`sulating a drug according to the conventional dissolution
`method. Specifically, if 200 mg of Ibuprofen is formulated
`in a soft capsule using the solvent system according to the
`present invention, it is possible to reduce the capsule filling
`material as small as 516 mg. However, if 200 mg of
`Ibuprofen is formulated according to the prior arts, it is
`difficult to expect improvement in the dissolution rate even
`though it is formulated in an amount less than 600 mg. As
`another example, if 250 mg of Naproxen is formulated by
`applying the system of the present invention, a capsule can
`be made to contain the capsule filling material in an amount
`of 800 mg. However, it is difficult to formulate a capsule
`with a volume of less than 1400 mg since the dissolution rate
`is significantly low.
`
`[0037] Therefore, the pharmaceutical preparation accord(cid:173)
`ing to the present invention and a solvent system therefor has
`the characteristics that the dissolution and disintegration
`rates and the bioavailability are improved, and a small-sized
`capsule that can be readily taken by a consumer was
`formulated for the first time.
`
`[0038] The representative examples of the acidic drugs
`which can be applied to the solvent system according to the
`present invention
`include Naproxen (C14H140 3 , M.W
`230.26), R,S-Ibuprofen (C13H180 2 , M.W 206.28), Dexibu(cid:173)
`profen(S-Ibuprofen, C13H180 2 , M.W 206.28), lndometha-
`
`cin (C19H16ClN0 4 , M.W 357.79), Acetaminophen (M.W
`151.17), Mefenamic acid (C15H15N0 2 , M.W 241.29), Chlo(cid:173)
`rocinnazine 2HC1 (C26H27N2 Cl. 2HC1, MW: 475.88), Loxo(cid:173)
`profen (C15H180 3 , MW: 246.31), Fenoprofen (C15H140 3 ,
`MW: 242.27), Ketoprofen (C16H140 3 , MW: 254.29), Pra(cid:173)
`noprofen (C15H13N0 3 , MW:255.27), Meclofenamic acid
`(C14H11 C12N0 2 , MW: 296.15) and salts thereof, Sulindac
`(C20H17F03 S, MW:356.42), Piroxicam (C15H13N3 0 4 S,
`MW:331.35), Meloxicam (C14H13N3 0 4 S2 , MW:351.41),
`(C13H11N3 0 4S2 , MW:337.38), Diclofenac
`Tenoxicam
`(C14H11 Cl2N0 2 ,
`MW:296.15),
`Aceclofenac
`(C16H13Cl2N0 4 ,
`MW:354.19),
`Rebamipide
`(C19H15ClN2 0 4 , MW:370.79),
`Enalapril
`maleate
`(C20H28N2 0 5 , MW:492.52), Captopril (C9 H15N0 3 S, MW:
`217.29), Ramipril (C23H32N2 0 5 MW:416.52), Fosinopril
`(C30H46N0 7P, MW:563.67), Benazepril
`(C24H28N2 0 5 ,
`MW:424.50), Quinapril (C25H30N2 0 5 , MW:474.99) hydro(cid:173)
`chloride, Temocapril (C23H28N205S2 MW:476.62), Cilaza(cid:173)
`pril (C22H31N3 0 5 MW:417.51), Lisinopril (C21H 31N3 0 5 ,
`MW:405.50), Valsartan (C24H29N5 0 3 , MW:435.53), Losa(cid:173)
`rtan potassium (C22H22ClKN6 0 MW:461.01), Irbesartan
`(C25H28N 60 MW:428.54), Cetirizine
`hydrochloride
`(C21H25ClN2 0 3 , MW:388.90), Diphenhydramine hydro(cid:173)
`chloride (C17H21 NO. HCl, MW: 291.82), Fexofenadine
`(C32H39N0 4 , MW:501.67), Pseudoephedrine hydrochloride
`201.70), Methylephedrine
`(C10H15NO HCl, MW:
`hydorchloride
`(C11H17NO.HC1, MW: 215.72), Dex(cid:173)
`tromethorphan hydrobromide (C18H25NO HEr H2 0, MW:
`370.33), Guaifenesin (C10H140 4 , MW: 198.22), Noscapine
`(C22H23N0 7 , MW: 413.43), Tri-metoquinol hydrocloride
`(C19H23N0 5 . HCl, MW: 399.87), Doxylamine succinate
`(C17H22N2 0,
`388.5), Ambroxol
`C4 H 60 4 , MW:
`(C13H18Br2 N2 0, MW: 378.11), Letosteine (C10H17N0 4S2 ,
`MW: 279.37), Sobrerol (C10H180 2 , MW: 170.25), Brom(cid:173)
`hexine hydrochloride (C14H20Br2 N2 HCl, MW: 412.59),
`Chlorpheniramine Maleate (C16H19ClN2 . C4H4 0 4 , MW:
`390.87) and optical isomers thereof, but are not limited
`thereto.
`
`[0039] The foregoing acidic drugs are contained in an
`amount of 0.1 to 70% by weight, preferably 10 to 55% by
`weight, based on the total weight of the capsule filling
`material.
`
`[0040] Hereinbelow,
`invention will be
`the present
`explained in detail, primarily referring to N aproxen that has
`the lowest dissolution rate among the previously listed
`acidic drugs. However, it will be apparent to those skilled in
`the art that the present invention is not limited thereto but
`can be applied to any of the hardly soluble acidic drugs.
`
`[0041] The solvent system according to the present inven(cid:173)
`tion comprises a cation acceptance as a component. The
`term "cation acceptance" used herein refers to anion species
`which can take an cation upon dissociation into an anion and
`a cation, Bronsted base and Lewis base which can take
`hydrogen ion, and its examples include any one selected
`from the group consisting of pharmaceutically acceptable
`basic compounds (for example, KOH, NaOH), metallic salts
`of weak acids (for example, sodium acetate, potassium
`acetate, potassium citrate, sodium citrate), amines (for
`example, prolamine, di-ethanolamine, mono-ethanolamine,
`tri-ethanolamine, methylglucamine), or amino acids (for
`example, lysine, threonine, cystein) and a mixture of one or
`more thereof, but are not limited thereto. These cation
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1010, Pg. 8 of 17
`
`

`

`US 2004/0157928 Al
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`Aug. 12, 2004
`
`4
`
`acceptances may increase the solubility of the acidic drugs
`by readily taking hydrogen ion in the carboxyl group of the
`acidic drug.
`
`preferably 5 to 30 and can be used alone or in combination
`of two or more. Preferred examples of such surfactants are
`as follows:
`
`[0042] Among the cation acceptances, hydroxide species
`that react with the acidic drug include sodium hydroxide
`(NaOH), potassium hydroxide (KOH), magnesium hydrox(cid:173)
`ide (Mg(OH)2 ), calcium hydroxide (Ca(OH) 2) and the like,
`with potassium hydroxide being the most preferred. Potas(cid:173)
`sium of the potassium hydroxide has an atomic number
`greater than sodium. In the same element group, as the
`atomic number
`is bigger,
`the
`ionization
`tendency
`is
`increased. This is because the distance between a nucleus
`and an electron in the outermost shell is far and the force of
`the nucleus pulling the electrons is weak, whereby the
`ionization can readily occur to form a bond with a negatively
`charged ion. For these reasons, the potassium hydroxide can
`advantageously be used in the preparation of a salt of the
`acidic drug in the ionized state.
`
`[0043] The basic compounds such as KOH and NaOH are
`used in an amount to make the hydroxyl ion (-OH) content
`of 0.2 to 1 mole per mole of the acidic group of the hardly
`soluble acidic drug. Especially, the hydroxide species are
`more preferably used in the same amount with water. If the
`hydroxide species are used in an excessive amount, the
`disintegration delay may occur due to the increase of pH.
`
`[0044] Among the foregoing cation acceptances, the
`metallic salts of weak acids are preferably used in an amount
`of 0.1 to 2 mole per mole of the acidic group of a hardly
`soluble acidic drug. If the amount exceeds the foregoing
`range, the disintegration delay may occur due to the increase
`of pH.
`
`[0045] Among the foregoing cation acceptances, the
`amines are used in an amount of 0.1 to 2 moles per mole of
`the acidic group of a hardly soluble acidic drug. Since the
`amines have abundant electrons in themselves, they can
`readily take cations. Accordingly, they can increase the
`ionization tendency of the acidic drug, thereby increasing
`solubility. If the amines are used in amount of over 2 moles
`with respect to the acidic drug, there is a problem of capsule
`stability associated with disintegration or dissolution, which
`makes it improper.
`
`[0046] The mixed use of the foregoing cation acceptances
`may result in more preferred results and this feature forms
`another preferred aspect of the present invention. When the
`foregoing cation acceptances are used in combination, the
`total amount of the mixed cation acceptances is used in the
`range of 0.1 to 2 moles per mole of the acidic group of a
`hardly soluble acidic drug. Upon the mixed use, the hydrox(cid:173)
`ide species may be more preferably used in the same amount
`with water and other cation acceptances can be used regard(cid:173)
`less of the amount of water and the hydroxide species.
`
`[0047]
`It is more preferable that the amount of water
`needed in the solvent system of the present invention is 50%
`or more for the cation acceptance.
`
`[0048]
`In the solvent system of the present invention, the
`surfactant serves as a co-solvent or a dissolution aid to
`promote drug dissolution and mainly comprises materials
`with the hydrophilic and hydrophobic properties. In particu(cid:173)
`lar, the surfactants for use in the present invention have a
`HLB(Hydrophilic Lipophilic Balance) value of 3 to 40,
`
`[0049]
`i) Reaction products of natural or hydroge(cid:173)
`nated vegetable oils and ethylene glycol; that is,
`polyoxyethylene glycolated natural or hydrogenated
`vegetable oils; for example, polyoxyethylene glyco(cid:173)
`lated natural or hydrogenated castor oils, such as the
`products commercially available under the trade
`name of Cremophor RH 40, Cremophor RH 60,
`Cremophor EL, Nikkol HC0-40, Nikkol HC0-60,
`etc., with Cremophor RH 40 and Cremophor EL
`being particularly preferred.
`
`[0050]
`ii) Polyoxyethylene sorbitan fatty acid esters;
`for example, mono- and tri-lauryl, palmityl, stearyl
`and oleyl esters of polyoxyethylene sorbitan fatty
`acids, such as products commercially available under
`the trade name of Tween, which includes Tween 20,
`21, 40, 61, 65, 80, 81, 85, 120, with Tween 20, Tween
`60 and Tween 80 being preferred.
`
`[0051]
`iii) Transesterification products of natural
`vegetable oil tri-glyceride and polyalkylene polyol;
`for example, commercially available surfactants
`such as Labrafil M 2125 CS, Labrafil M 1944 CS, or
`Labrafac CC, Labrafac PG; and Labrasol.
`
`[0052]
`iv) Polyoxyethylene fatty acid esters, for
`example, polyoxyethylene(8) stearate (trade name:
`Myrj 45), polyoxyethylene(30) mono-laurate (trade
`name: Tagat L), polyoxyethylene(20) stearate (trade
`name: Marlosol 1820), polyoxyethylene(15) oleate
`(trade name: Marlosol OL 15), trade name: Cetiol
`HE; polyoxyethylene stearic acid esters,
`for
`example,
`polyoxyethylene-polyoxypropylene
`copolymers, such as products of the trade name of
`Pluronic and Emkalyx; polyoxyethylene-polyox(cid:173)
`ypropylene block copolymers, for example, products
`commercially available under the trade name Polox(cid:173)
`amer, specifically Poloxamer 188, 124, 237, 338,
`407, mono-, di- and mono-/di-glyceride, particularly,
`esterification products of caprylic acid or capric acid
`and glycerol, surfactants mainly comprising caprylic
`acid/capric acid mono-
`and di-glyceride,
`for
`example, Imbitor.
`
`[0053] v) Sorbitan fatty acid esters; for example,
`sorbitan mono-laurate, sorbitan mono-palmitate, sor(cid:173)
`bitan mono-stearate, sorbitan tri -stearate, sorbitan
`mono-oleate, sorbitan tri-oleate, etc., such as prod(cid:173)
`ucts commercially available under the trade name of
`Span; polyethylene glycol fatty acid esters, which
`are classified to stearates, laurates, oleates according
`to the bonded fatty acid, with polyethylene glycol
`mono-oleate being preferred, for example, trade
`name of MY0-2, MY0-6, MY0-10 etc.
`
`[0054] vi) Propylene glycol mono- and di-fatty acid
`ester, for example, propylene glycol dicaprylate,
`such as trade name of MIGLYOL 840; propylene
`glycol dilaurate, propylene glycol hydroxystearate,
`propylene glycol iso-stearate, propylene glycol lau(cid:173)
`rate, propylene glycol lysine oleate, propylene glycol
`stearate, etc., for example, trade name of Sefsol 218
`and Capryol 90, Capryol PGMC, Lauro glycol FCC
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1010, Pg. 9 of 17
`
`

`

`US 2004/0157928 Al
`
`Aug. 12, 2004
`
`5
`
`or Lauro glycol 90; MAISINE 35-1 (glyceryl mono(cid:173)
`linolate), PECEOL (glyceryl mono-oleate), GELU(cid:173)
`CIRE 44/14 (lauroyl polyoxyl-32 glyceride) and
`GELUCIRE 33/01 (fatty acid glycerol ester),
`[0055] vii) Pharmaceutically acceptable C1_5 alkyl or
`tetrahydrofurfuryl di- or partial-ether of low molecu(cid:173)
`lar mono- or poly-oxy-alkanediol, for example,
`diethylene glycol monoethyl ether, commercially
`available under the trade name Transcutol;
`[0056] viii) Polyoxyethylene fatty acid ethers, for
`example, polyoxyethylene (10) oleyl ether (trade
`name: Brij 96), polyoxyethylene (15) oleyl ether
`(trade name: Volpo 015), polyoxyethylene (30) ole(cid:173)
`ine ether (trade name: Marlowet OA30), polyoxy(cid:173)
`ethylene (20) C12-C14 fatty acid ether).
`[0057]
`ix)
`Polyoxyethylene-polyoxypropylene
`copolymer, for example, trade name Syperonic PE
`L44, Syperonic F127.
`[0058] Among them, the surfactant is preferably selected
`from the group consisting of Cremophor RH40 (Polyoxyl40
`hydrogenated castor oil), Cremophor EL (Polyoxyl35 castor
`oil), Labrasol (polyethylene glycol caprylate/caprate), Tran(cid:173)
`scutol