(12) United States Patent
`Sawyer et al.
`
`111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US006383515B2
`US 6,383,515 B2
`*May 7, 2002
`
`(10) Patent No.:
`(45) Date of Patent:
`
`(54) SOLVENT SYSTEM FOR ENHANCING
`SOLUBILITY
`
`(76)
`
`Inventors: MaryJean Sawyer, 420 Cardinal La.,
`Bedminster, NJ (US) 07921; Anthony
`Efiong Ekpe, 16 Colgate Rd.,
`Maplewood, NJ (US) 07040;
`Maw-Sheng Wu, 6 McVickers La.,
`Mendham, NJ (US)
`
`( *) Notice:
`
`This patent issued on a continued pros(cid:173)
`ecution application filed under 37 CFR
`1.53( d), and is subject to the twenty year
`patent term provisions of 35 U.S.C.
`154(a)(2).
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 09/322,819
`
`(22) Filed:
`
`May 28, 1999
`
`Int. Cl? .................................................. A61K 9/64
`(51)
`(52) U.S. Cl. ....................... 424/456; 424/451; 424/455;
`514/772.2
`(58) Field of Search ................................. 424/451, 455,
`424/456
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`6/1985 Arizono et a!. ............... 424/81
`4,525,348 A
`9/1987 Lohner eta!. .............. 424/456
`4,690,823 A
`10/1987 Henmi eta!. ............... 424/455
`4,701,327 A
`11/1987 Cohen eta!. ............... 424/456
`4,708,834 A
`12/1987 Begum eta!. .............. 424/455
`4,713,246 A
`1!1989 Patel .......................... 424/456
`4,798,725 A
`4,868,207 A * 9/1989 Shi-jie ........................ 514/464
`5,071,643 A
`12/1991 Yu eta!. ..................... 514/570
`11/1994 Yu et a!. ..................... 424/455
`5,360,615 A
`5,505,961 A
`4/1996 Shelley eta!. .............. 424/451
`
`* cited by examiner
`
`Primary Examiner-Thurman K. Page
`Assistant Examiner-Lilian a Dinola-Baron
`(74) Attorney, Agent, or Firm-John S. Child, Jr.
`
`(57)
`
`ABSTRACT
`
`A pharmaceutically acceptable solution with a medicament
`suitable for filling a soft gelatin capsule is made from a
`solvent. The solvent contains a polymer, such as polyethyl(cid:173)
`ene glycol, and an acid salt of a compound having 3 or more
`carbon atoms, and a salt such as sodium propionate. The
`solvent may optionally contain a cosolvent, such as dimethyl
`isosorbide. The medicament may preferably comprise an
`analgesic such as aspirin or naproxen.
`
`3,557,280 A
`
`1!1971 Weber et a!.
`
`................. 424/80
`
`13 Claims, No Drawings
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1015, Pg. 1 of 9
`
`

`

`US 6,383,515 B2
`
`1
`SOLVENT SYSTEM FOR ENHANCING
`SOLUBILITY
`
`BACKGROUND OF THE INVENTION
`
`1. Field of the Invention
`The invention relates to medicinal solutions suitable for
`encapsulation in soft gelatin capsules. More particularly, the
`invention relates to pharmaceutically acceptable solvent
`systems capable of producing a highly concentrated solution 10
`of a medicament, such as acetaminophen or naproxen, for
`use in a soft gelatin capsule.
`2. Description of Related Art
`Soft gelatin capsules or "softgels" are, as their name
`implies, gelatin capsules that are softer than conventional
`caplets, capsules or tablets. They are commonly used to
`encapsulate liquids containing an active ingredient or ingre(cid:173)
`dients. Softgels are used to contain consumables, such as
`vitamins or pharmaceuticals, including products in the over(cid:173)
`the-counter market. Softgels are also used in many other
`industries, and have been used to encapsulate such diverse
`substances as industrial adhesives and bath oils.
`In the pharmaceutical industry, softgels provide many
`benefits over conventional liquid and solid administration
`vehicles. They dissolve in the stomach faster than com(cid:173)
`pressed tablets. Tablets must dissolve in the stomach or
`intestines and so generally retard the speed of onset of a
`medicament administered in a tablet form. Tablets are also
`generally unsuited for administration of liquids. Hard gelatin
`or starch-based capsules may be used for liquid or solid 30
`delivery systems. But, capsules are generally not appropriate
`for liquids because the hard gelatin or starch capsules may
`be either softened or entirely dissolved by a liquid medica(cid:173)
`ment. In addition, some air is usually trapped in a hard
`gelatin capsule, where a liquid "fill" is put into the capsule. 35
`This air bubble can affect the active ingredients and detract
`from the appearance of the product. Softgels are better than
`direct liquid administration because liquids spill, and some
`medicaments may have unacceptable or unpleasant taste
`even with taste masking agents. Softgels, on the other hand, 40
`dissolve rapidly in the stomach and the body quickly absorbs
`the liquid interior of the softgel, so softgels offer an attrac(cid:173)
`tive means of administering a medicament.
`Not all liquids may be enclosed in a softgel. Liquids
`containing more than about 20% water by weight are
`generally not enclosed in softgels, because the water tends
`to dissolve the gelatin shell. Propylene glycol, glycerin, low
`molecular weight alcohols, ketones, acids, amines, and
`esters all tend to degrade or dissolve the softgellayer gelatin
`to some extent. Thus, formulations that are enclosed in a
`softgel cannot contain significant amounts of many well(cid:173)
`known solvents.
`Softgels are also somewhat sensitive to pH, and generally
`require a pH in the encapsulated liquid from about 2.5 to 55
`about 7.5. Highly acidic liquids may hydrolyze the gelatin,
`resulting in leaks, while basic liquids may tan the gelatin,
`resulting in decreased solubility of the gelatin shell.
`Pharmaceutical liquids are usually enclosed in softgels as
`either viscous solutions or suspensions. Suspensions are
`pharmaceutically less desirable because they can settle dur(cid:173)
`ing manufacture, which leads to a less uniform product. If a
`suspension is used, the solid particles in a suspension should
`be smaller than about 80 mesh, otherwise the softgel filling
`equipment might not function optimally.
`Suitable softgel solutions, however, can be difficult to
`achieve. The walls of a softgel are thicker than the walls of
`
`2
`a caplet or a hard gelatin capsule. The softgel should be
`small enough for patient acceptance. The thickness of the
`walls reduces the available space for the medicament. But,
`the softgel must contain sufficient quantities of the medica-
`5 ment to be effective. One approach, of course, is simply to
`require the consumer to swallow more than one softgel to
`achieve any adequate dose of the medicament. Consumers,
`however, prefer taking one or two softgels, tablets or cap-
`sules and resist taking more than three.
`The solution in the softgel must thus be highly concen(cid:173)
`trated. High concentration levels, though, strain the ability
`of conventional solvent systems to dissolve a sufficient
`quantity of the pharmaceutical agent. A strong solvent, on
`the other hand, can degrade the gelatin coating. So, a
`15 frequent problem in softgel applications is dissolving the
`active ingredient or ingredients in a sufficiently small
`amount of solvent to provide a potent dose of the medica(cid:173)
`ment in the softgel. Solvent systems must be used that are
`tailored to the specific needs of a specific medicament or
`20 blend of medicaments. For example, U.S. Pat. No. 3,557,280
`to Weber et al., issued January 1971, used a magnesium salt,
`polyvinylpyrrolidone and water to dissolve oxytetracycline
`for injection or oral liquid administration. U.S. Pat. No.
`5,071,643 to Yu et al., issued Dec. 10, 1991 and U.S. Pat.
`25 No. 5,360,615 also to Yu et al., issued Nov. 1, 1994, used
`polyethylene glycol and an acid or a base to dissolve
`ibuprofen, naproxen, indomethacin or acetaminophen
`(among others).
`Another solvent system, found in U.S. Pat. No. 5,505,961
`to Shelley et al., issued Apr. 9, 1996, used polyethylene
`glycol and sodium or potassium acetate to enhance the
`solubility of acetaminophen.
`Despite these efforts, there is still a strong need in the art
`for solvent systems that can dissolve large amounts of a
`medicament, especially without the addition of large
`amounts of an acid or base.
`
`SUMMARY OF THE INVENTION
`
`50
`
`45
`
`It is an object of the present invention to provide a solvent
`system capable of producing a highly concentrated solution
`of a pharmaceutical agent suitable for encapsulation into a
`softgel of suitable size without neutralizing large amounts of
`the agent.
`It is a further object of the present invention to create such
`a solvent system that can be safely consumed by human
`beings.
`It is a further object of the present invention to use such
`a solvent system to create a highly concentrated solution of
`a medicament, like acetaminophen or naproxen, suitable for
`use as a fill in a softgel. About a one ml softgel should
`encapsulate about 325 mg of acetaminophen or about 220
`mg of naproxen.
`It is a further object of the present invention to create a
`solvent system for enhancing the solubility of medicaments,
`including such over-the-counter medicaments as pain reliev(cid:173)
`ers and cold remedies.
`It is an advantage of the invention that one of the
`60 ingredients in the solvent system may itself be an antifungal
`agent, thereby increasing the safety of the solvent system
`during storage and handling.
`Additional objects and advantages of the invention will be
`set forth in part in the description that follows, and in part
`65 will be obvious from the description.
`To achieve the foregoing objects and in accordance with
`the purpose of the invention, as embodied and broadly
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1015, Pg. 2 of 9
`
`

`

`US 6,383,515 B2
`
`3
`described herein, the invention provides a pharmaceutically
`acceptable solution comprising a medicament and a solvent
`system. The solvent system comprises a low molecular
`weight polymer and a salt of an organic acid containing at
`least three carbon atoms.
`To further achieve the foregoing objects and in accor(cid:173)
`dance with the purpose of the invention, as embodied and
`broadly described herein, the invention provides a method
`for dissolving a large amount of a medicament in a small
`amount of solvent. The solvent comprises a low molecular
`weight polymer and a salt of an organic acid containing at
`least three carbon atoms.
`
`DESCRIPTION OF THE PREFERRED
`EMBODIMENTS
`
`We will now describe the preferred embodiments of the
`invention.
`The formulation of the invention comprises three types of
`systems: (a) a solvent system; (b) a solvent system and a
`medicament; and (c) a solvent system, at least one medica- 20
`ment dissolved in the solvent system, and a softgel sur(cid:173)
`rounding the medicament and solvent system.
`The solvent system of the invention comprises a low
`molecular weight polymeric material and a salt of an organic 25
`acid containing at least three carbon atoms. The system may
`also contain additional ingredients as set out below.
`One part of the solvent system of the invention is a low
`molecular weight polymeric material. As used herein, "a low
`molecular weight" polymer is any polymer that is liquid or 30
`semi-solid at about room temperature and pressure when
`combined in a solvent system or any polymer that can
`dissolve in a limited amount of water to form a solvent
`system. The particular identity of the polymeric entity
`selected as the solvent will guide one skilled in the art to the 35
`appropriate molecular weight for the polymer. Since the
`polymer will be ingested into the human body, it must be
`safe and nontoxic (at least when used in the amounts
`contemplated herein). While the polymer need not be orga(cid:173)
`noleptically pleasing, the polymer preferably does not cause 40
`any adverse side reactions or other detrimental effect on
`humans upon ingestion.
`Linear or branched polymers, of course, generally do not
`have a single molecular weight. Rather, each strand in a
`polymer sample will have a different length and the 45
`"molecular weight" of a polymer sample will be the average
`molecular weight of the strands.
`Acceptable polymers that may be used in the invention
`include polyalkylene glycols and polyvinyl pyrollidones and
`analogs thereof, including various copolymers, polymer 50
`blends and modified polymers thereof. The polymers of the
`invention may also include polymeric materials that are not
`ordinarily thought of as polymers, such as glycerin and
`propylene glycol. The preferred polymers of the invention
`are polyols, such as glycerin, propylene glycol and poly- 55
`alkylene glycols. More preferred are polyethylene glycols
`and polypropylene glycols. More preferably, the polyethyl(cid:173)
`ene glycols of the invention have a molecular weight of less
`than about 1500, since polyethylene glycol1500 is reported
`to be solid at room temperature. (Molecular weights of about 60
`1500 or above are not excluded from the invention to the
`extent that the polymer may be semi-solid, liquid or soluble
`in limited amounts of water.) Most preferably, the molecular
`weight of the polyethylene oxide is from about 400 to about
`600 daltons, and the most preferred embodiment of the 65
`invention uses polyethylene glycol having a molecular
`weight of about 600. The solvent may comprise mixtures of
`
`4
`materials as well. For example, a polyethylene glycol having
`a molecular weight of about 600 may be obtained by using
`PEG 600 or about a 50/50 mixture of PEG 400 and PEG 800.
`The polymeric material preferably comprises from about
`5 10% by weight to about 70% by weight of the solution of the
`invention. More preferably, the polymeric material com(cid:173)
`prises from about 15% by weight to about 65% by weight of
`the solution and even more preferably, the polymeric mate(cid:173)
`rial comprises from about 20% by weight to about 55% by
`10 weight of the solution. Most preferably, the polymeric
`material comprises from about 30% by weight to about 50%
`by weight of the solution of the invention. When blends of
`the polymers are used as a solvent, it is preferable, but not
`critical, that one species of polymer predominates. Thus, in
`15 one preferred embodiment of the invention, the solvent
`system comprises from about 15% to about 65% by weight
`polyethylene glycol600 and from 0% to about 5% by weight
`of (and more preferably from 0% to about 2% by weight)
`propylene glycol.
`In addition to the polymeric material, the invention also
`comprises a salt of an organic acid containing at least three
`carbon atoms. The salt helps to ionize the medicament,
`especially where the medicament is capable of forming a
`zwitterion, without relying on strong acids or bases.
`Preferred cations for the salt are monovalent and divalent
`cations that are nontoxic and acceptable for human con(cid:173)
`sumption. These cations include, but are not limited to,
`sodium, potassium, and calcium ions. Alkali cations are
`preferred, and sodium is the most preferred cation.
`The anion of the salt is an organic acid anion containing
`at least three carbon atoms. Acceptable acid anions include
`those capable of forming a nontoxic salt with any of the
`cations of the invention. Although the preferred acid anions
`are from saturated aliphatic acids having from three to six
`carbon atoms, other acids are not excluded from the scope
`of the invention. Aromatic acids, saturated acids having
`more than six carbon atoms, and unsaturated acids having
`more than three carbon atoms may be used, so long as the
`acid forms a nontoxic salt. More preferred acids include
`mono, di- and tri-carboxylic acids having three to six carbon
`atoms, including propionic acid, pyruvic acid, citric acid,
`and butanoic acid. Propionic acid is the most preferred
`because it has antifungal properties.
`In a highly preferred embodiment of the invention, the salt
`is a sodium propionate salt that is added to the solution of the
`invention as a salt/water solution. Preferred concentrations
`of the salt solution are from about 40% by weight to a
`saturated solution of the salt in water.
`The pH of this propionate solution may be adjusted by the
`addition of small amounts of propionic acid, usually no more
`than about 1-2% by weight of the propionate solution. So,
`the numbers in the examples may be slightly incorrect.
`The salt may comprise from about 2% by weight to about
`40% by weight of the solution of the invention. More
`preferably, the salt comprises from about 4% to about 35%
`by weight of the solution of the invention, and even more
`preferably, from about 4% by weight to about 25% by
`weight of the solution of the invention. Preferably the pH is
`adjusted in the salt/water solution to provide acceptable pH
`limits in the softgel.
`The solvent system of the invention may also contain
`additional ingredients such as cosolvents, including dim(cid:173)
`ethyl isosorbide, oils, including soybean oil, and water. The
`cosolvent may comprise from 0% by weight to about 30%
`by weight of the solution of the invention, and more pref-
`erably from about 5% by weight to about 20% by weight of
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1015, Pg. 3 of 9
`
`

`

`US 6,383,515 B2
`
`15
`
`6
`administered. Different medicaments, such as naproxen,
`aspirin and acetaminophen, have different chemical struc(cid:173)
`tures and different affinities for various solvent combina-
`tions. Highly concentrated solutions of medicaments, such
`as aspirin and naproxen, require a solvent system tailored to
`the specific needs of the medicament.
`The solution of the invention may be prepared through
`mixing of the ingredients. This mixing takes place prefer(cid:173)
`ably at an elevated temperature and with applied shear.
`While the applied shear does not necessarily allow for
`greater solubility of any ingredient, it appears to provide
`better stability of the solution during handling and storage.
`Preferably, the solvent is prepared first and the medicament
`is then added to the solvent. The salt is then also added
`slowly to help dissolve the medicament. It appears that if the
`salt is added too quickly, ionization of the medicament does
`not take place and the material does not form a successful
`solution. The process may be carried out in whole or in part
`in a nitrogen atmosphere if the presence of oxygen might
`discolor or otherwise damage any ingredient in the solution.
`Preferred embodiments of the invention have been pre(cid:173)
`pared as described in the examples below. A solution of
`polyethylene glycol600 and, optionally, dimethyl isosorbide
`is prepared in a glass flask, and is stirred at about 250 rpm,
`and heated to about 50° C. (An acceptable solution may be
`prepared without dimethyl isosorbide.) The flask may then
`be deaerated with nitrogen. Acetaminophen or another medi-
`cament is added and a stopper is used to cover the flask.
`Next, the sodium propionate solution is added dropwise,
`using a metered flow control device. The formulation is
`30 again blanketed with nitrogen and then stirred at about 300
`rpm with heat until clear, which usually requires from about
`30 to about 120 minutes. Another preferred embodiment
`incorporates shear to help the materials to blend more
`quickly and thoroughly.
`
`EXAMPLES
`
`The following examples are intended to demonstrate
`some embodiments of the invention without limiting the
`scope or spirit of the invention. Due to rounding, total
`40 percentages for some of the formulations described below
`do not equal100%. In some examples the amount of added
`propionate solution was recorded in mls. of solution added.
`This recorded number was converted to grams using an
`approximate density of 1.17 to 1.18
`
`5
`the solution of the invention. Most preferably, the cosolvent
`is dimethyl isosorbide and comprises from about 5% by
`weight to about 10% by weight of the solution of the
`invention. Water may comprise from 0% by weight to about
`25% by weight of the solution of the invention. Oils may 5
`comprise from 0% to about 20% by weight of the solution
`of the invention, and more preferably from 0% to about 15%
`by weight of the solution of the invention. In the examples
`that follow, water is added as part of a sodium propionate
`solution that is added to the solvent system. In some of these 10
`examples, the reported amounts in grams were calculated
`from the density and volume of the propionate solution
`added.
`The medicament of the invention may be any
`medicament, but the softgels of the invention are of primary
`benefit in human consumption, so the medicaments of the
`invention are preferably those intended for use by humans.
`Preferred medicaments are those used in over-the-counter
`treatments of coughs, colds and other common ailments.
`Thus, highly preferred medicaments include pain relievers, 20
`such as aspirin, acetaminophen, naproxen, ibuprofen and
`other nonsteroidal anti-inflammatory drugs, as well as the
`so-called "Cox-2" inhibitors. Other highly preferred medi(cid:173)
`caments include, but are not limited to, cough suppressants,
`such as dextromethorphan, decongestants, such as 25
`pseudoephedrine, and antihistamines, such as chlorphe(cid:173)
`niramine and doxylamine compounds. Medicaments that
`form zwitterions when dissolved with the salts of the inven(cid:173)
`tion are most highly preferred.
`The total amount of medicaments of the invention may
`comprise from about 25% by weight of the solution up to the
`amount that will form a fully saturated solution, usually up
`to about 70% by weight of the solution. Preferably, however,
`the medicaments comprise from about 30% by weight to
`about 55% by weight of the solution of the invention. Of 35
`course, dosage levels will be adjusted to reflect the needs of
`the patient, not the needs of the solvent.
`Consumer preference suggests that clear or at least trans(cid:173)
`lucent solutions should be used in softgels. The solvent
`system of the present invention may be adjusted to provide
`such a clear solution acceptable to consumers. In the
`examples that follow, many of the solutions have a color.
`The color may be significantly reduced by carrying out the
`solution process in the absence of oxygen. While the 45
`examples used a nitrogen blanket, the solution was exposed
`to air while various materials were added, which affected the
`final color of the solution.
`The medicament should remain in solution to achieve the
`benefits of the invention, and the solution should remain
`stable over time and under conditions normally encountered
`in consumer applications. The solution disclosed in the
`present invention has been found stable and robust in a
`number of tests. For instance, the solution has been placed
`"on the shelf" at room temperature for extended periods of
`time, and has remained clear and stable, without precipita(cid:173)
`tion of the medicament. Moreover, the solution has been
`subjected to alternating refrigeration and room temperature
`conditions, and the medicament has not crystallized, and has
`remained stable and clear.
`The solution has been placed in softgels successfully, at
`least on an experimental level. The gelatin in a softgel may
`be any known on the art. Suitable results have been achieved
`with Type A gelatin, bloom strength 150. Hydrophilic soft(cid:173)
`gels are preferred.
`The selection of ingredients to be used in the solvent
`system will, of course, depend on the medicament to be
`
`Example 1
`
`A solution was prepared having the formulation set forth
`in Table 1 as follows. The polyethylene glycol, dimethyl
`50 isosorbide and soybean oil were combined in a 250 ml flask.
`This mixture was heated to about 45° C. and stirred at about
`250 rpm. The flask was blanketed with nitrogen gas, and
`acetaminophen was added as quickly as possible to reduce
`discoloration of the solution. A solution containing the water
`55 and the sodium propionate was slowly added to the mixture.
`A clear, brown colored solution was obtained. Due to
`rounding, the percentages do not add up to 100%.
`
`60
`
`65
`
`TABLE 1
`
`Formulation of Example 1
`
`Ingredient
`
`Amount
`
`Weight Percent (%)
`
`Polyethylene glycol 600
`Dimethyl isosorbide
`Water
`Soybean oil
`
`25 g
`15 g
`5 g
`16 g
`
`25%
`15%
`5%
`16%
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1015, Pg. 4 of 9
`
`

`

`US 6,383,515 B2
`
`7
`
`TABLE 1-continued
`
`Formulation of Example 1
`
`Ingredient
`
`Amount
`
`Weight Percent(%)
`
`Sodium propionate
`Acetaminophen
`Chlorpheniramine
`Pseudoephedrine
`Dextromethorphan
`Doxylamine succinate
`Propylene glycol
`
`5.5 g
`33 g
`0 g
`0 g
`0 g
`0 g
`0 g
`
`5.5%
`33%
`0%
`0%
`0%
`0%
`0%
`
`8
`was prepared by mixing at room temperature until dissolved.
`The polyethylene glycol and the dimethyl isosorbide were
`put into a 125-ml glass-stoppered Erlenmeyer flask. The
`mixture was stirred and heated and blanketed with nitrogen.
`5 The acetaminophen was then added, and the sodium propi(cid:173)
`onate solution was then added. A clear, pink colored solution
`was obtained. After placing the solution in a freezer for four
`hours the solution was removed and allowed to return to
`room temperature. No crystallization was observed.
`
`10
`
`TABLE 4
`
`Formulation of Example 4
`
`15
`
`Example 2
`A formulation was prepared with the ingredients set forth
`in Table 2. The polyethylene glycol and dimethyl isosorbide
`were mixed, and a slurry of the sodium propionate and water
`was added to the mixture. This mixture was heated to 45° C.
`and stirred to dissolve the slurry. The acetaminophen was
`added in 5-gram portions, and complete solubility was 20
`obtained, providing a clear, light pink colored solution.
`Although some crystallization was observed upon cooling,
`only minimal precipitation had been observed after storage
`for ten days at room temperature.
`
`Ingredient
`
`Amount
`
`Weight Percent(%)
`
`Polyethylene glycol 600
`Dimethyl isosorbide
`Water
`Soybean oil
`Sodium propionate
`Acetaminophen
`Chlorpheniramine
`Pseudoephedrine
`Dextromethorphan
`Doxylamine succinate
`Propylene glycol
`
`39.6 g
`6.2 g
`10 g
`0 g
`7.9 g
`33 g
`0 g
`0 g
`0 g
`0 g
`1.8 g
`
`40%
`6%
`10%
`0%
`8%
`34%
`0%
`0%
`0%
`0%
`2%
`
`TABLE 2
`
`Formulation of Example 2
`
`Ingredient
`
`Amount
`
`Weight Percent (%)
`
`Polyethylene glycol 600
`Dimethyl isosorbide
`Water
`Soybean oil
`Sodium propionate
`Acetaminophen
`Chlorpheniramine
`Pseudoephedrine
`Dextromethorphan
`Doxylamine succinate
`Propylene glycol
`
`35 g
`5 g
`4 g
`0 g
`5 g
`32.5 g
`0 g
`0 g
`0 g
`0 g
`0 g
`
`43%
`6%
`5%
`0%
`6%
`40%
`0%
`0%
`0%
`0%
`0%
`
`25
`
`30
`
`35
`
`40
`
`Example 3
`A formulation was prepared with the ingredients set forth
`in Table 3. Polyethylene glycol 600 and dimethyl isosorbide
`were combined, heated to 45° C., and stirred. The sodium
`propionate was mixed with the water to form a solution and 45
`added to the solvents. Acetaminophen was added, and a
`clear, pink colored solution was obtained.
`
`TABLE 3
`
`Formulation of Example 3
`
`Ingredient
`
`Amount
`
`Weight Percent(%)
`
`Polyethylene glycol 600
`Dimethyl isosorbide
`Water
`Soybean oil
`Sodium propionate
`Acetaminophen
`Chlorpheniramine
`Pseudoephedrine
`Dextromethorphan
`Doxylamine succinate
`Propylene glycol
`
`21 g
`6 g
`15 g
`0 g
`12g
`51 g
`0 g
`0 g
`0 g
`0 g
`0 g
`
`20%
`6%
`14%
`0%
`11%
`49%
`0%
`0%
`0%
`0%
`0%
`
`Example 4
`A formulation was prepared with the ingredients set forth
`in Table 4. A solution of the sodium propionate in the water
`
`Example 5
`
`A formulation was prepared with the ingredients set forth
`in Table 5. A sodium propionate solution was prepared by
`dissolving 40 grams of sodium propionate in 50 mls of
`water. Polyethylene glycol and dimethyl isosorbide were
`then placed in a 250-ml distillation flask, stirred and heated.
`The acetaminophen was then added and nitrogen was blown
`into the stopper of the flask to keep oxygen away from the
`solution. 20-21 ml of the propionate solution were then
`added to the flask and stirring continued until a clear, pink
`colored solution was obtained. This solution was blanketed
`with nitrogen, stoppered and frozen for 16 hours. The
`solution then returned to room temperature, and slight
`crystal formation was observed on the surface of the solu(cid:173)
`tion.
`
`TABLE 5
`
`Formulation of Example 5
`
`Ingredient
`
`Amount
`
`Weight Percent(%)
`
`Polyethylene glycol 600
`Dimethyl isosorbide
`Water
`Soybean oil
`Sodium propionate
`Acetaminophen
`Chlorpheniramine
`Pseudoephedrine
`Dextromethorphan
`Doxylamine succinate
`Propylene glycol
`
`42.4 g
`9.94 g
`13.7 g
`0 g
`llg
`32.7 g
`0 g
`0 g
`0 g
`0 g
`0 g
`
`39%
`9%
`12%
`0%
`10%
`30%
`0%
`0%
`0%
`0%
`0%
`
`Example 6
`
`50
`
`55
`
`60
`
`A formulation was prepared with the ingredients set forth
`in Table 6. A sodium propionate solution was prepared by
`dissolving 40 grams of sodium propionate in 50 mls of
`water. Polyethylene glycol and dimethyl isosorbide were
`65 then placed in a 250-ml distillation flask, stirred and heated.
`The acetaminophen was then added and nitrogen was blown
`into the stopper of the flask to keep oxygen away from the
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1015, Pg. 5 of 9
`
`

`

`US 6,383,515 B2
`
`9
`solution. 20-21 ml of the propionate solution were then
`added to the flask and stirring continued until a clear, pink
`colored solution was obtained. This solution was blanketed
`with nitrogen, stoppered and frozen for 16 hours. The
`solution was then returned to room temperature, and slight
`crystal formation was observed on the bottom of the solu(cid:173)
`tion.
`
`TABLE 6
`
`Formulation of Example 6
`
`Ingredient
`
`Amount
`
`Weight Percent (%)
`
`Polyethylene glycol 600
`Dimethyl isosorbide
`Water
`Soybean oil
`Sodium propionate
`Acetaminophen
`Chlorpheniramine
`Pseudoephedrine
`Dextromethorphan
`Doxylamine succinate
`Propylene glycol
`
`29.5 g
`19.9 g
`13.7 g
`0 g
`llg
`33.2 g
`0 g
`0 g
`0 g
`0 g
`0 g
`
`27%
`19%
`13%
`0%
`10%
`31%
`0%
`0%
`0%
`0%
`0%
`
`Example 7
`
`A formulation was prepared with the ingredients set forth
`in Table 7. A sodium propionate solution was prepared by
`dissolving 40 grams of sodium propionate in 50 mls of
`water. Polyethylene glycol and dimethyl isosorbide were
`then placed in a 250-ml distillation flask, stirred and heated.
`The acetaminophen was then added and nitrogen was blown
`into the stopper of the flask to keep oxygen away from the
`solution. 20-21 ml of the propionate solution were then
`added to the flask and stirring continued until a clear, pink
`colored solution was obtained. This solution was blanketed
`with nitrogen, stoppered and frozen for 16 hours. The
`solution was then allowed to return to room temperature, and
`no crystal formation was observed.
`
`TABLE 7
`
`Formulation of Example 7
`
`Ingredient
`
`Amount
`
`Weight Percent (%)
`
`Polyethylene glycol 600
`Dimethyl isosorbide
`Water
`Soybean oil
`Sodium propionate
`Acetaminophen
`Chlorpheniramine
`Pseudoephedrine
`Dextromethorphan
`Doxylamine succinate
`Propylene glycol
`
`27.2 g
`28.8 g
`13.7 g
`0 g
`llg
`33 g
`0 g
`0 g
`0 g
`0 g
`0 g
`
`24%
`25%
`12%
`0%
`10%
`29%
`0%
`0%
`0%
`0%
`0%
`
`Example 8
`
`10
`stirring continued overnight. A cloudy, light yellow solution
`was obtained. An additional 5 ml of the sodium propionate
`solution was added, the solution was reheated and stirring
`continued until a clear, light orange colored solution was
`5 obtained.
`
`TABLE 8
`
`Formulation of Example 8
`
`Ingredient
`
`Amount
`
`Weight Percent(%)
`
`Polyethylene glycol 600
`Dimethyl isosorbide
`Water
`Soybean oil
`Sodium propionate
`Acetaminophen
`Chlorpheniramine
`Pseudoephedrine
`Dextromethorphan
`Doxylamine succinate
`Propylene glycol
`
`38.2 g
`12.9 g
`15.1 g
`0 g
`10.5 g
`37.6 g
`0.24 g
`3.2 g
`0 g
`0 g
`0 g
`
`34%
`11%
`12%
`0%
`9%
`31%
`0.2%
`2.8%
`0%
`0%
`0%
`
`Example 9
`
`A formulation was prepared with the ingredients set forth
`in Table 9. The polyethylene glycol was charged into a
`250-ml distillation flask and heated to 50° C. and stirred. The
`acetaeminophen was added to the flask, and the flask was
`blanketed with nitrogen while stirring and heating contin(cid:173)
`ued. 30 mls of the sodium propionate solution were added,
`the nitrogen blanket was reapplied and stirring continued for
`two hours until a light pink solution was obtained. After the
`solution was kept in the freezer overnight and then placed in
`warm water some crystals appeared, so an additional 5 ml of
`the sodium propionate solution was added under heat and
`stirring to redissolve the crystals.
`
`TABLE 9
`
`Formulation of Example 9
`
`Ingredient
`
`Amount
`
`Weight Percent(%)
`
`Polyethylene glycol 600
`Dimethyl isosorbide
`Water
`Soybean oil
`Sodium propionate
`Acetaminophen
`Chlorpheniramine
`Pseudoephedrine
`Dextromethorphan
`Doxylamine succinate
`Propylene glycol
`
`50.1 g
`0 g
`22.9 g
`0 g
`18.4 g
`33.5 g
`0 g
`0 g
`0 g
`0 g
`0 g
`
`40%
`0%
`18%
`0%
`15%
`27%