111111
`
`1111111111111111111111111111111111111111111111111111111111111111111111111111
`US 20060099246Al
`
`(19) United States
`c12) Patent Application Publication
`Tanner et al.
`
`(10) Pub. No.: US 2006/0099246 A1
`May 11, 2006
`(43) Pub. Date:
`
`(54) NON-GELATIN SOFT CAPSULE SYSTEM
`
`Publication Classification
`
`(76)
`
`Inventors: Keith E. Tanner, Safety Harbor, FL
`(US); Rickey S. Shelley, Largo, FL
`(US); Norman S. Stroud, Safety
`Harbor, FL (US); Elizabeth
`Youngblood, Valrico, FL (US)
`
`Correspondence Address:
`CARDINAL HEALTH
`7000 CARDINAL PLACE
`LEGAL DEPARTMENT - INTELLECTUAL
`PROPERTY
`DUBLIN, OH 43017 (US)
`
`(21) Appl. No.:
`
`10/984,205
`
`(22) Filed:
`
`Nov. 8, 2004
`
`(51)
`
`Int. Cl.
`A61K 9148
`(2006.01)
`(52) U.S. Cl. .............................................................. 424/451
`
`(57)
`
`ABSTRACT
`
`A non-gelatin encapsulation system for liquid filled soft
`capsules, by nature of the carrier, the cationic-ionic balance
`of the carrier and the active ingredients, or the concentration
`of the active ingredients and excipients, are difficult or
`impossible to commercially encapsulate in gelatin capsules.
`In particular, the system is adapted for the encapsulation of
`highly basic, or alkaline, fills. The system provides for a
`predominantly starch and gelling carrageenan based shell,
`which displays high resistance to both concentrated fills and
`to alkaline fills, in particular, to those fills which contain the
`salt or salts of weak acids and strong bases.
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1016, Pg. 1 of 11
`
`

`

`US 2006/0099246 AI
`
`May 11,2006
`
`1
`
`NON-GELATIN SOFT CAPSULE SYSTEM
`
`TECHNICAL FIELD
`
`[0001] The instant invention relates to a system for encap(cid:173)
`sulating certain materials that are traditionally difficult or
`impossible to encapsulate in gelatin capsules. More specifi(cid:173)
`cally, the invention is directed to a system for encapsulating
`highly basic liquid formulations in a non-gelatin soft cap(cid:173)
`sule.
`
`BACKGROUND OF THE INVENTION
`
`[0002] Experience has long shown that pharmaceuticals or
`other items for human or animal consumption may be safely
`and conveniently packaged in a hard or soft gelatin (softgel)
`shell. Gelatin is a substantially pure protein food ingredient,
`obtained by the thermal denaturation of collagen, which is
`the most common structural material and most common
`protein in animals. Gelatin forms thermally reversible gels
`with water, and the gel melting temperature ( <35° C.) is
`below that ofhuman body temperature (37° C.), which gives
`gelatin products unique properties, such as reversible sol-gel
`transition states at near physiologic temperatures.
`
`[0003] Gelatin is an amphoteric protein with an isoionic
`point between 5 and 9, depending on raw material and
`method of manufacture. Type A gelatin, with an isoionic
`point of 7 to 9, is derived from collagen with acid pretreat(cid:173)
`ment. Type B gelatin, with an isoionic point of 4.8 to 5.2, is
`the result of alkaline pretreatment of the collagen. Like its
`parent protein collagen, gelatin is unique in that in contains,
`approximately, 16% proline, 26% glycine, and 18% nitro(cid:173)
`gen. Gelatin is not a complete protein food because the
`essential amino acid tryptophan is missing and the amino
`acid methionine is present only at a low level.
`
`[0004] There are a large number of processes used in the
`manufacture of gelatin and the raw materials from which it
`is derived, which includes demineralized bone, pigskin,
`cowhide and fish. Gelatin can be derived from any edible
`material containing collagen. For reasons of economy, gela(cid:173)
`tin can be most practically be derived from collagen sources
`which would normally require refining before consumption
`or which would otherwise make up protein-containing waste
`material destined for animal feeds, agricultural fertilizers, or
`for other industries.
`
`[0005] Gelatin capsules are traditionally divided into two
`general groups; hard shell gelatin capsules and soft gelatin
`capsules (softgels). In hard shell gelatin capsules, the cap(cid:173)
`sule is in equilibrium with a relative humidity of less than
`20%; they are formulated with a low ratio of dry plasticizer
`to dry gelatin (low amounts of plasticizer); and are tradi(cid:173)
`tionally made of two separately formed, cooperating, tele(cid:173)
`scoping shells. On the other hand, softgels are most com(cid:173)
`monly in equilibrium with a relative humidity of between
`20% and 30%, are formulated with a high ratio of dry
`plasticizer to dry gelatin (higher amounts of plasticizer); and
`are traditionally formed in a unitary process such as the
`rotary die encapsulation process described below.
`
`[0006] Filled one-piece soft capsules or softgels have been
`widely known and used for many years and for a variety of
`purposes and 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 enclose or
`
`contain consumable materials such as vitamins and pharma(cid:173)
`ceuticals in a liquid vehicle or carrier.
`
`[0007] Encapsulation within a soft capsule of a solution or
`dispersion of a nutritional or pharmaceutical agent in a
`liquid carrier offers many advantages over other dosage
`forms, such as compressed, coated or uncoated solid tablets,
`or bulk liquid preparations. Encapsulation of a solution or
`dispersion permits accurate delivery of a unit dose, an
`advantage which becomes especially important when rela(cid:173)
`tively small amounts of the active ingredient must be
`delivered, as in the case of certain hormones. Such unifor(cid:173)
`mity is more difficult to achieve via a tableting process
`wherein solids must be uniformly mixed and compressed, or
`via incorporation of the total dose of active ingredient into
`a bulk liquid carrier which must be measured out prior to
`each oral administration.
`
`[0008] Encapsulation of drugs in soft capsules further
`provides the potential to improve the bioavailability of
`pharmaceutical agents. Active
`ingredients are rapidly
`released in liquid form as soon as the shell ruptures. Com(cid:173)
`plete disintegration of the capsule is not necessary for the
`active ingredients to become available for absorption, unlike
`the case oftableted compositions. Also, relatively insoluble
`active ingredients can be dispersed in a liquid carrier to
`provide faster absorption. A typical example involves a
`solution of a hydrophobic drug in a hydrophilic solvent.
`Upon ingestion, the shell ruptures in the stomach and the
`hydrophilic solution dissolves in the gastric juice. Acid
`soluble compounds remain in solution and are readily avail(cid:173)
`able for rapid absorption. Acid insoluble compounds may
`precipitate temporarily, in the form of a fine particle disper(cid:173)
`sion, but then redissolve quickly to give a solution with good
`bioavailability.
`
`[0009] Soft capsules, most commonly, soft gelatin cap(cid:173)
`sules, provide a dosage form which is readily accepted by
`patients, since the capsules are easy to swallow and need not
`be flavored in order to mask the unpleasant taste of the active
`agent. Soft capsules are also more easily transported by
`patients than bulk liquids, since only the required number of
`doses need be removed from the package.
`
`[0010] Traditionally, both soft and hard-shell capsules
`have been manufactured using mammalian gelatin as the
`material of choice for producing the capsule envelope. The
`rotary die process developed by Robert Scherer in 1933 for
`producing one piece soft capsules utilizes the unique prop(cid:173)
`erties of gelatin to enable a continuous soft capsule manu(cid:173)
`facturing process. The inventive encapsulation system dis(cid:173)
`closed in this patent application is especially useful in the
`rotary die method of soft capsule manufacture.
`
`[0011] Conventional manufacturing of soft capsules using
`the rotary die process utilizes mammalian gelatin in a
`process well known to those of skill in the art. Dry gelatin
`granules are combined with water and suitable plasticizers
`and the combination is then mixed and heated under vacuum
`to form a molten gelatin mass. The gelatin mass is held in its
`molten state while being formed or cast into films or ribbons
`on casting wheels or drums. The films or ribbons are fed
`under a wedge and between rotary encapsulation dies.
`Within the encapsulation dies, capsules are simultaneously
`formed, in pockets in the dies, from the films or ribbons, then
`filled, cut, and sealed. The seals are formed via a combina(cid:173)
`tion of pressure and heat as the capsule is filled and cut.
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1016, Pg. 2 of 11
`
`

`

`US 2006/0099246 AI
`
`May 11,2006
`
`2
`
`Rotary die manufacture of soft gelatin capsules is disclosed
`in detail in The Theory and Practice of Industrial Pharmacy
`(Lachman, Lieberman and Kanig, Editors), 3rd Edition,
`published by Lea & Febiger. A good description of gelatin
`encapsulation techniques can also be found in WO 98/42294
`(PCT/GB98/00830).
`
`[0012] Gelatin formulations used to produce films suitable
`for making capsules within the rotary die process typically
`contain between 25% to 45% by weight mannnalian gelatin.
`Levels below 25% by weight tend to lead to poor sealing of
`the capsule. The physical properties of the gelatin film are
`critical to the economic production of soft capsules. For
`example, the film must be strong enough to survive manipu(cid:173)
`lation in the encapsulation machine, provide good sealing
`properties at temperatures below the melting point of the
`film, evidence rapid dissolution in gastric juices, and have
`sufficient elasticity to allow for the formation of the capsule.
`
`[0013] There are, however, significant problems associ(cid:173)
`ated with gelatin capsules. In the case of gelatins derived
`from mannnalian gelatin, there are concerns regarding the
`possible transmission of prions that are believed responsible
`for syndromes such as bovine spongiform encephalopathy
`(BSE or "mad cow" disease) and Jacob-Creutzfeldt Syn(cid:173)
`drome. There are also ethical, cultural, dietary, and religious
`restrictions in various parts of the world against products
`derived from certain animals. To answer concerns about the
`safety and consumer acceptability of mammalian gelatins,
`gelatins have been derived from fish sources, however, fish
`gelatins have particular fabrication requirements and are
`likely to become increasingly expensive with the depletion
`of the world's fish resources.
`
`[0014] Regardless of the ultimate source of the gelatin
`from either mannnal or fish sources, none of these
`approaches have answered what may be the most funda(cid:173)
`mental problem regarding gelatin encapsulation, namely,
`that not all substances and compounds may be successfully
`encapsulated, in a gelatin capsule.
`
`[0015] Not all liquids are suitable as vehicles or carriers
`for the fill of a softgel. For example, water, propylene glycol,
`glycerin and low molecular alcohols, ketones, acids, amines
`and esters cannot be filled in softgels by themselves, or may
`only be present in small amounts. In particular, concentra(cid:173)
`tions of water in the fill of greater than 20% by weight will
`dissolve the gelatin shell. Liquids that are suitable for filling
`softgels vary from water immiscible liquids such as veg(cid:173)
`etable oils, aromatic oils, aromatic and aliphatic hydrocar(cid:173)
`bons, chlorinated hydrocarbons, ethers and esters, to water
`miscible nonvolatile liquids. Examples of other acceptable
`carriers include polyethylene glycols and nonionic surfac(cid:173)
`tants and other pharmaceutically acceptable solvent systems.
`
`[0016] Even if the fill liquid is amenable to gelatin encap(cid:173)
`sulation, there are specified limitations to the use of certain
`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 leaking, whereas at
`pH's greater than 7.5, the gelatin can also be hydrolyzed.
`Moreover, emulsions of oil/water or water/oil are not suit(cid:173)
`able for softgel encapsulation because the emulsions even(cid:173)
`tually break down, releasing water which dissolves the
`gelatin shell. The solvent or carrier in some cases must have
`sufficient solvating power to dissolve a large amount of the
`
`pharmaceutical agent to produce a highly concentrated solu(cid:173)
`tion, and yet not hydrolyze, dissolve, or discolor the gelatin
`shell.
`[0017] Even when provided a suitable carrier and suitable
`agent for encapsulation, there can be problems in successful
`commercial encapsulation. One problem occurs with agents
`of low solubility that require a relatively large volume of
`solvent for solubilization, leading to the necessity for a large
`capsule. Often, it is not possible to dissolve the pharmaceu(cid:173)
`tical agent in a volume of solvent small enough to produce
`a softgel that is appropriate from the standpoint of econom(cid:173)
`ics and patient acceptance.
`[0018] Recently, various systems for increasing the solu(cid:173)
`ingredients have been
`bility of low-solubility active
`described as, for example, in U.S. Pat. Nos. 5,071,643 and
`5,360,615 to Yu, eta!. These systems involve the titration of,
`as appropriate, acid or alkali into polyethylene glycol (PEG)
`containing a low-solubility pharmaceutical agent. In particu(cid:173)
`lar, the creation of a salt of a weak acid and strong alkali,
`such as potassium hydroxide or sodium hydroxide, mark(cid:173)
`edly increases the solubility of the pharmaceutical agent in
`PEG. However, by converting a portion of the pharmaceu(cid:173)
`tical agent to the salt of a weak acid and strong alkali and
`thereby increasing the solubility, hydroxide ion (-OH) is
`necessarily present as a reacting species and is available for
`degradation of the gelatin. This may occur by hydrolysis of
`the gelatin, a disruption of the ionic bonding between the
`gelatin helices, or by a combination of the two, along with
`other possible mechanisms. In fact, it is a long-established
`and widely held tenet of pharmaceutical chemistry that such
`salts cannot be encapsulated in gelatin capsules, unless they
`are highly diluted.
`[0019] Thus, under the prior art, the pharmaceutical chem(cid:173)
`ist is often faced with a true dilemma, desiring to use alkali
`to increase the solubility of a recalcitrant pharmaceutical
`agent in order to formulate a capsule small enough for
`commercial acceptance and/or to stabilize the drug sub(cid:173)
`stance; while at the same time being forced to restrict the use
`of alkali lest the capsule be impermissibly degraded.
`[0020] Particular note must be taken of the need to for(cid:173)
`mulate capsules that satisfY commercial, rather than theo(cid:173)
`retic, utility. While it may be possible to formulate certain
`basic fills in gelatin capsules as an initial matter of encap(cid:173)
`sulation, such formulations, as will be described below, are
`unable to satisfy the stability standards for commercial
`pharmaceutical products. Therefore, as will be seen below,
`it has, in the prior art, remained extremely difficult as a
`practical matter to encapsulate many basic substances in soft
`gelatin capsules.
`[0021] A prototypical example of a pharmaceutical agent
`that has proven difficult to encapsulate in soft gelatin cap(cid:173)
`sules is acetaminophen (APAP). Utilizing the enhanced
`solubility system described in U.S. Pat. Nos. 5,071,643 and
`5,360,615 to Yu, eta!.; Shelley eta!. found, as taught in U.S.
`Pat. No. 5,505,961, that the sodium hydroxide or potassium
`hydroxide required to solubilize the acetaminophen at very
`high concentrations (those greater than about 27% by
`weight), increased the pH of the PEG solution to greater than
`12, resulting in the degradation of the acetaminophen and
`the dissolving of the softgel shell.
`[0022] By adding, inter alia, propylene glycol and poly(cid:173)
`vinylpyrrolidone, Shelley et a!. were able to achieve con-
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1016, Pg. 3 of 11
`
`

`

`US 2006/0099246 AI
`
`May 11,2006
`
`3
`
`centrations of acetaminophen in a stable gelatin capsule
`preparation to 40% by weight, but not significantly more.
`Such an advance had the effect of obtaining the same size
`softgel for a 325 mg dose as for a 250 mg dose softgel
`product under the prior art. While significant, this still falls
`short of the desired dosage capabilities, which range even
`higher in the case of prescription formulated acetaminophen.
`
`[0023] Such a problem in achieving suitable dosage sys(cid:173)
`tems wherein the active or actives must be formulated as a
`high concentration preparation is not restricted to acetami(cid:173)
`nophen, but also includes, by way of illustration and not
`limitation, such well-known drugs as ibuprofen, naproxen,
`pseudoephedrine hydrochloride, dextromethorphan hydro(cid:173)
`bromide, doxylamine succinate, guafenesin, diphenhy(cid:173)
`dramine, aspirin, and caffeine; as well as certain dosage
`forms and concentrations of ranitidine, cimetidine, cele(cid:173)
`coxib, ritonavir, and fexofenadine; in addition to many
`others and combinations of the above enumerated drugs.
`
`[0024] What has been needed, and heretofore unavailable,
`is a system for encapsulating those pharmaceutical agents
`and carriers that have heretofore proved refractory to encap(cid:173)
`sulation in gelatin capsules, due either to the effect of the
`concentration of the agent or carrier, or the basic nature of
`the fill. The present invention has solved this problem by a
`novel and unexpected use of a drug delivery system of a
`non-gelatin capsule shell resistant to alkali and, in one
`embodiment, a partially neutralized drug in which the pro(cid:173)
`vision of the salt of a weak acid and a strong alkali produced
`significantly high drug concentrations in acceptable quanti(cid:173)
`ties of solvent.
`
`SUMMARY OF THE INVENTION
`
`In its most general configuration, the present inven(cid:173)
`[0025]
`tion advances the state of the art with a variety of new
`capabilities and overcomes many of the shortcomings of the
`prior art soft capsules. In its most general sense, the present
`invention overcomes the shortcomings and limitations of the
`prior art in any of a number of generally effective compo(cid:173)
`sitions and methods.
`
`[0026] The instant invention provides for a non-gelatin
`encapsulation system for certain difficult to encapsulate
`products, particularly, for those capsule fill formulas that, by
`nature of the carrier, the cationic-ionic balance of the carrier
`and the active ingredients, or the concentration of the active
`ingredients and excipients, are difficult or impossible to
`commercially encapsulate in gelatin capsules. The system
`provides for a predominantly starch and gelling carrageenan
`based capsule, which displays the novel and unexpected
`quality of high resistance to concentrated alkaline fills, in
`particular, to those fills which contain the salt or salts of
`weak acids and strong bases. The instant invention is par(cid:173)
`ticularly suitable for fills with a pH greater than about 7.5;
`more preferably fills with a pH greater than 8.0, and most
`preferably, for fills with a pH between 8.0 and 12.0.
`
`[0027] Active ingredients that require high concentrations
`per dose, are inherently alkaline, or require formulation as a
`salt, include but are not limited to: ibuprofen, naproxen,
`acetaminophen, pseudoephedrine hydrochloride, dex(cid:173)
`tromethorphan hydrobromide,
`doxylamine
`succinate,
`guafenesin, diphenhydramine, aspirin, caffeine, ranitidine,
`cimetidine, celecoxib, ritonavir, and fexofenadine, and com(cid:173)
`binations of these and other agents. The use of the system of
`
`the instant invention has allowed the successful manufacture
`of softgel dosage forms of concentrated solutions of ibu(cid:173)
`profen, naproxen, and acetaminophen, containing larger
`dosages of the active ingredient of these compounds than
`has heretofore been possible in a commercially successful
`softgel of therapeutically reasonable size.
`
`[0028] What is disclosed, therefore, is a soft capsule
`system for encapsulating chemical compounds, comprising
`a shell comprising a modified starch and a gelling carrag(cid:173)
`eenan; and a fill, the fill including at least one active
`ingredient dissolved or dispersed in a carrier, wherein the fill
`has a pH greater than about 7.5. More preferably, the fill has
`a pH greater than about 8.0; and most preferably, the fill has
`a pH between about 8.0 and 12.0.
`
`[0029] The shell of the system further comprises a mixture
`of starch, gelling carrageenan, water, a plasticizer and a
`buffer, wherein the starch and the gelling carrageen are at a
`weight to weight ratio of between at least 1.5 to 1 and 5.0 to
`1. More preferably, the starch and the gelling carrageen are
`at a weight to weight ratio of between at least 2 to 1; and
`most preferably, the starch and the gelling carrageen are at
`a weight to weight ratio of at least 3 to 1.
`[0030] The gelling carrageenan may comprise iota-carra(cid:173)
`geenan, kappa-carrageenan, and mixtures thereof. The
`starch is a modified starch selected from the group consist(cid:173)
`ing ofhydroxypropylated tapioca starch, hydroxypropylated
`maize starch, acid thinned hydroxypropylated com starch,
`native potato starch, pregelatinized modified corn starches;
`and wherein said starch has a hydration temperature below
`about 90 degrees Centigrade.
`[0031] The active agent may be ibuprofen and the ibupro(cid:173)
`fen may present in the capsule in a weight to weight ratio of
`at least 40%. The active agent may be acetaminophen, and
`the acetaminophen may be present in the capsule in a weight
`to weight ratio of at least 40%. The active agent may be
`naproxen, and the naproxen may be present in the capsule in
`a weight to weight ratio of at least 20%.
`[0032] Furthermore, the fill may comprise an acidic active
`ingredient and an alkali agent sufficient to partially neutral(cid:173)
`ize a portion of the active agent, by forming an equilibrium
`between the acidic active ingredient, and the salt of the
`acidic agent and alkali agent; and the degree of neutraliza(cid:173)
`tion may also be between 40% and 100% of the acidic active
`ingredient.
`[0033] By way of example and not limitation, the active
`agent or agents may also be selected from the group con(cid:173)
`sisting of pseudoephedrine hydrochloride, dextromethor(cid:173)
`phan hydrobromide, doxylamine succinate, guafenesin,
`diphenhydramine, aspirin, caffeine, ranitidine, cimetidine,
`celecoxib, ritonavir, and fexofenadine and combinations
`thereof.
`[0034] The system according to the invention can have
`alkali added to the fill formulation to enhance the stability
`and/or solubility of the active ingredient. In similar fashion,
`an acidic agent can be added to the fill, provided however
`that the final pH of the fill formulation is above 7.5. This
`would be for highly basic active ingredients.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`[0035] The encapsulation system of the instant invention
`provides a significant advancement in the state of the art.
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1016, Pg. 4 of 11
`
`

`

`US 2006/0099246 AI
`
`May 11,2006
`
`4
`
`The preferred embodiments of the inventive encapsulation
`system accomplish this by new and novel elements that
`demonstrate previously unavailable but preferred and desir(cid:173)
`able capabilities. The detailed description set forth below is
`intended merely as a description of the presently preferred
`embodiments of the invention, and is not intended to rep(cid:173)
`resent the only form in which the present invention may be
`constructed or utilized. The description sets forth the func(cid:173)
`tions, means, and methods of implementing the invention in
`connection with the illustrated embodiments. It is to be
`understood, however, that the same or equivalent functions
`and features may be accomplished by different embodiments
`that are also intended to be encompassed within the spirit
`and scope of the claims.
`
`[0036]
`Initial experimentation was prompted by the obser(cid:173)
`vation that a suspension of a proprietary acerola extract,
`representing a salt of a weak acid and a strong alkali, quickly
`degraded a sheet of gelatin capsule material made by the
`traditional art, while it appeared to have no effect on a sheet
`of non-gelatin encapsulation material made principally of
`starch and gelling carrageenan, according to the method of
`Tanner et a!., as taught in U.S. Pat. Nos. 5,376,688 and
`6,582,727 (incorporated herein in their entirety by refer(cid:173)
`ence). As would be understood by one skilled in the art, all
`reference in the following specification and claims to starch
`refers to gelling starches, and all references to carrageenan
`refers to gelling carrageenans.
`
`Initial Experimentation on the Effects of Alkali on
`Encapsulation Films
`
`[0037] The observation that a formulation containing a
`basic extract of acerola did not appear to affect the non(cid:173)
`gelatin film while quickly degrading a gelatin film prompted
`an examination of the effect of concentrated alkali on such
`films. While it is generally held that starch is itself suscep(cid:173)
`tible to degradation by alkali, the results seen were an
`apparent paradox to this past belief, suggesting that addi(cid:173)
`tional mechanisms, and a mechanism hitherto undiscovered,
`were responsible for the observed resistance of the predomi(cid:173)
`nantly starch film to alkaline materials. Therefore, experi(cid:173)
`mentation was undertaken to examine the effect of highly
`concentrated alkali on gelatin films, starch films, gelling
`carrageenan films, and the combined starch/gelling carrag(cid:173)
`eenan film.
`
`[0038] Films were cast by techniques well-known in the
`art with the compositions set forth in Table I.
`
`TABLE I
`
`Film Compositions for Testing with Concentrated Alkali
`
`Gelatin Film
`
`Ingredient
`
`Amount, % by weight
`
`Gelatin
`Polysorb ®
`Purified Water, USP
`
`38
`21
`41
`
`Starch Film
`
`Ingredient
`
`Amount % by weight
`
`Hydroxypropylated starch
`Polysorb ®
`
`31
`12.5
`
`TABLE !-continued
`
`Film Compositions for Testing with Concentrated Alkali
`
`Glycerol
`di-Sodium Phosphate
`Purified Water, USP
`
`12.5
`0.7
`43.3
`
`Carrageenan Film
`
`Ingredient
`
`Amount, % by weight
`
`Iota-Carrageenan
`Polysorb ®
`Glycerol
`di-Sodium Phosphate
`Purified Water, USP
`
`7.5
`12.5
`12.5
`0.7
`66.8
`
`Starch/Gelling Carrageenan Film
`
`Ingredient
`
`Amount, % by weight
`
`Hydroxypropylated starch
`Iota-Carrageenan
`Polysorb ®
`Glycerol
`di-Sodium Phosphate
`Purified Water, USP
`
`23.5
`7.5
`12.5
`12.5
`0.7
`43.3
`
`[0039] The films were cast and allowed to form and set. A
`rectangular section of each film was cut, removed, and
`placed onto a wire test tube rack. Depressions were allowed
`to form in sections of each film. These depressions were then
`filled with concentrated alkali in the form of a pellet of
`potassium hydroxide. The test rig was then placed in and
`maintained in an oven at 30° C. and 95% relative humidity
`(RH.). Interaction between the alkali and the film was
`monitored at regular intervals.
`
`[0040] Results:
`
`[0041]
`In the gelatin film, the pockets were destroyed
`within two hours. The residue around the burned-through
`pockets was sticky or stringy in quality, indicative of break(cid:173)
`down of the gelatin.
`
`[0042]
`In the starch film, there was no observed effect in
`the first four hours. At the five hour examination interval, the
`pockets were observed to exhibit sagging or dimpling, and
`had lost opacity, while the "control" area of the film
`remained semi-opaque. All pockets burned through within
`24 hours of initiation of the experiment. The residues
`surrounding the burned-through pockets were discolored
`brown and were sticky or stringy, indicative of starch
`breakdown.
`
`[0043]
`In the gelling carrageenan film, there was no
`observed effect after five hours. After 30 hours, the pockets
`remained intact with no destruction of structure observed.
`
`[0044]
`In the starch/gelling carrageenan film, the film was
`regularly monitored for nine days. Throughout, and at the
`conclusion of the study, the pockets were found to be
`undamaged with no destruction of structure observed.
`
`[0045] On the basis of this experiment, the following
`determinations can be made. Gelatin is rapidly degraded by
`strong alkali, while starch is also quickly degraded, but
`slightly less rapidly than gelatin. Carrageenan is unaffected
`by strong alkali, at least over the time span of this experi(cid:173)
`ment. Surprisingly, and central to the instant invention, the
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1016, Pg. 5 of 11
`
`

`

`US 2006/0099246 AI
`
`May 11,2006
`
`5
`
`starch/gelling carrageenan film was also unaffected by the
`strong alkali, even though the major component of the film,
`by a 3:1 ratio over the gelling carrageenan, was hydrox(cid:173)
`ypropylated starch, which, as noted, is very susceptible to
`attack by alkali. The ratio of starch to carrageenan is found
`effective in a ratio of between 1.5 to 1 and 5 to 1, more
`preferably in a ratio of greater than 2: 1, and most preferably
`in a ratio greater than 3: 1. Furthermore, while the experi(cid:173)
`mentation was conducted with iota-carrageenan,
`it is
`believed that similar results would be obtained with kappa(cid:173)
`carrageenan and mixtures of iota- and kappa-carrageenan.
`The surprising conclusion is that there appears to be a
`synergistic relationship between starch and gelling carrag(cid:173)
`eenan, that, when the two are combined into a film, serves
`to protect the starch of the film from degradation by alkali.
`
`[0046] This experiment suggested the possibility that cer(cid:173)
`tain drug formulations, particularly those with alkaline prop(cid:173)
`erties, which had long been thought to be difficult or
`impossible to encapsulate, might, in a properly designed
`system, be amenable to stable and commercial production in
`a soft capsule.
`
`EXAMPLE 1
`
`Ibuprofen
`
`[0047] Experimentation was undertaken regarding achiev(cid:173)
`ing commercially successful formulations of ibuprofen
`when the ibuprofen was concentrated above a level previ(cid:173)
`ously consistent with success in the prior art. At the onset,
`formulations were prepared to determine the concentration
`of ibuprofen above which it was not possible, from a
`commercial perspective, to prepare stable preparations in a
`traditional soft gelatin capsule.
`
`Ibuprofen is 2-( 4-isobutylphenyl)-propionic acid.
`[0048]
`It is a weak carboxylic acid that is traditionally administered
`in doses of 200 mg for over-the-counter (OTC) preparations,
`or 400 mg for prescription use. In order to achieve a solution
`in a suitable sized soft capsule that is chemically stable,
`formulators have developed a mixed ibuprofen and potas(cid:173)
`sium ibuprofen solution in a polyethylene glycol solvent
`system, as taught in U.S. Pat. Nos. 5,071,643; 5,360,615;
`and 5,376,688. Typically, for this type of dosage form
`(softgel capsule), the dosage form must be chemically and
`physically stable for a period of not less than 6 months at 40°
`C. and 75% RH (relative humidity). If a product meets this
`quality specification, that is, it is chemically and physically
`stable under such accelerated testing for six months, it is
`highly predictive that the product will be stable for at least
`two years at normal shelf storage temperatures. On the other
`hand, if a product fails under such accelerated stability
`testing at the one month test interval, or any shorter time
`period; it will almost certainly exhibit the same failure at
`normal shelf storage temperatures.
`
`[0049] Experimentation was undertaken to assess the
`effect of salt concentration, that is, to determine the relative
`susceptibility of gelatin and non-gelatin capsules to 100%
`neutralized potassium ibuprofen in polyethylene glycol 600
`(PEG 600) at varying drug loading solutions, in an accel(cid:173)
`erated stability test protocol (40° C.-75% RH). Along with
`gelatin films made to standard formulations that are well(cid:173)
`known in the art (i.e., films that are identical in composition
`to the films used to manufacture capsules using the rotary die
`
`encapsulation process )(Table II), non-gelatin starch/gelling
`carrageenan films were formed from the following compo(cid:173)
`sitions, as described in Table III.
`
`TABLE II
`
`Gelatin Capsule Film Formulation
`(Wet-gel Gel Mass)
`
`Ingredient
`
`Amount, % by weight
`
`Gelatin
`Polysorb ®
`Purified water
`
`TOTAL:
`
`38