PCT
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`WO 99/66904
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`(51) International Patent Classification 6 :
`A61K 9/16, 9/50
`
`Al
`
`(11) International Publication Number:
`
`(43) International Publication Date:
`
`29 December 1999 (29.12.99)
`
`(21) International Application Number:
`
`PCT/US98/17120
`
`(22) International Filing Date:
`
`18 August 1998 (18.08.98)
`
`(30) Priority Data:
`09/104,952
`
`25 June 1998 (25.06.98)
`
`us
`
`(71) Applicant: THERATECH, INC. [US/US]; Suite 100, 417
`Wakara Way, Salt Lake City, UT 84108 (US).
`
`(72) Inventors: PATEL, Phenil, J.; 740 University Village, Salt
`Lake City, UT 84108 (US). ACHARYA, Ramesh; 3176
`Carrigan Canyon, Salt Lake City, UT 84109 (US). DA VE,
`Sirish, C.; 7611 South Toni Circle, Salt Lake City, UT
`84121 (US).
`
`(74) Agents: WESTERN, M., Wayne et al.; Thorpe, North &
`Western, L.L.P., P.O. Box 1219, Sandy, UT 84091-1219
`(US).
`
`(81) Designated States: AL, AM, AT, AU, AZ, BA, BB, BG, BR,
`BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE,
`GH, GM, HR, HU, ID, IL, IS, JP, KE, KG, KP, KR, KZ,
`LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW,
`MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ,
`TM, TR, TT, UA, UG, UZ, VN, YU, ZW, ARIPO patent
`(GH, GM, KE, LS, MW, SD, SZ, UG, ZW), Eurasian patent
`(AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European patent
`(AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT,
`LU, MC, NL, PT, SE), OAPI patent (BF, BJ, CF, CG, CI,
`CM, GA, GN, GW, ML, MR, NE, SN, TD, TG).
`
`Published
`With international search report.
`
`(54) Title: INCORPORATION OF LATENT ACID SOLUBILIZING AGENTS IN COATED PELLET FORMULATIONS TO OBTAIN
`pH INDEPENDENT RELEASE
`
`(57) Abstract
`
`This invention is directed to a composition and method for the sustained delivery of an orally administered pharmaceutical agent
`where said agent has a pH dependent solubility profile. A pH independent release for drugs with pH dependent solubility is accomplished
`through the incorporation of a latent acid member with the pharmaceutical agent in the core of the tablet or pellet formulation which
`maintains the microenvironmental pH within and around the tablet or pellet in the solubility pH range of the pharmaceutical agent.
`
`KVK-TECH EXHIBIT 1034
`
`

`

`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`
`AL
`AM
`AT
`AU
`AZ
`BA
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`CI
`CM
`CN
`cu
`CZ
`DE
`DK
`EE
`
`Albania
`Armenia
`Austria
`Australia
`Azerbaijan
`Bosnia and Herzegovina
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`Cote d'Ivoire
`Cameroon
`China
`Cuba
`Czech Republic
`Germany
`Denmark
`Estonia
`
`ES
`FI
`FR
`GA
`GB
`GE
`GH
`GN
`GR
`HU
`IE
`IL
`IS
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LC
`LI
`LK
`LR
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Ireland
`Israel
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyzstan
`Democratic People's
`Republic of Korea
`Republic of Korea
`Kazakstan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`LS
`LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SG
`
`Lesotho
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`The former Yugoslav
`Republic of Macedonia
`Mali
`Mongolia
`Mauritania
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`
`SI
`SK
`SN
`sz
`TD
`TG
`TJ
`TM
`TR
`TT
`UA
`UG
`us
`uz
`VN
`YU
`zw
`
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`Turkmenistan
`Turkey
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`Uzbekistan
`Viet Nam
`Yugoslavia
`Zimbabwe
`
`

`

`PCT/US98/17120
`WO 99/66904
`INCORPORATION OF LATENT ACID SOLUBILIZING AGENTS IN
`COATED PELLET FORMULATIONS TO OBTAIN pH INDEPENDENT
`RELEASE
`
`5
`
`BACKGROUND OF THE INVENTION
`
`The present invention relates to the controlled in vivo release of an active
`
`drug having pH dependent solubility from pellet formulations, comprised of a solid
`
`core containing the drug, a latent acid solubilizing agent, and an outer rate
`
`10
`
`controlling polymeric membrane. Because the drug has a pH dependent solubility,
`
`the pellet formulation contains one or more latent acid solubilizing agents that
`
`hydrolyze and alter the microenvironmental pH such that the drug becomes soluble
`
`even where the surrounding pH would tend to limit or inhibit drug solubility.
`
`Several illnesses, such as hypertension and angina pectoris, require
`
`15
`
`continuous and constant controlled drug release at therapeutic levels.
`
`In such
`
`instances, medications must be administered at consistent intervals, e.g. every six to
`
`eight hours, so as to maintain a therapeutically effective blood concentration of the
`
`active agent. When using medications such as diltiazem, which has a short half-life
`
`in blood of approximately three to four hours, such administration becomes even
`
`20
`
`more inconvenient. Such frequent administration times render the treatment
`
`annoying to the patient and impractical to administer, particularly during the night.
`
`Furthermore, after each administration of an immediate release form of such
`
`medications, the metabolic system undergoes a succession of rapidly increasing,
`
`followed by rapidly decreasing, plasma concentrations of the pharmaceutical agent
`
`25
`
`or drug. Thus, the patient being treated and the targeted organ, e.g., the cardiac
`
`system, are successively subjected to plasma drug levels above and then below the
`
`desired therapeutic level. When plasma drug levels are higher than desired there are
`
`obvious disadvantages, i.e. waste of drug, possibility of toxicity, development of
`
`drug resistance, and the like. On the other hand, when plasma levels are lower than
`
`30
`
`desired the drug may be ineffective or of marginal benefit. Obviously, it would be
`
`beneficial to maintain plasma drug levels as close to the optimal therapeutic level as
`
`possible.
`
`

`

`WO 99/66904
`
`PCT/US98/17120
`
`2
`
`A drug that has pH dependent solubility usually shows a pH dependent
`
`release rate relative to the formation of its corresponding salt species. Examples of
`
`such drugs include but are not limited to verapamil, diltiazem, albuterol, propranolol,
`
`bromocriptine, chlorphenaramine, prochlorperazine, dextromethorphan, enalapril,
`
`5
`
`labetalol,
`
`nicardipine,
`
`pentazocine, phenylpropanolamine,
`
`promethazine,
`
`diphenhydramine, metoclopramide, selegiline, timolol, trimethobenzamide, and
`
`quinidine, etc. These drugs contain a basic side chain moiety such that, at basic pHs,
`
`the drug is charge neutral and therefore is less soluble in aqueous systems. Indeed,
`
`such drugs are soluble only if ionized, such as when an acidic salt is formed.
`
`10
`
`Therefore, pH dependent drugs, such as enumerated herein, require the continued,
`
`consistent formation of a salt of the drug so as to ensure hydrophilic solubility and
`
`thus bioavailability. Unfortunately, the digestive tract does not favor the use of the
`
`acidic salts of these drugs. The digestive tract is known to vary in pH from about 1
`
`to 2 in the stomach to a neutral or even a basic pH in the duodenum and small and
`
`15
`
`large intestines. This wide variation of pH renders the acid soluble drugs less and
`
`less soluble, and hence less bioavailable, as they traverse the digestive tract.
`
`It has been historically problematic to achieve a controlled, sustained release
`
`of a pharmaceutical agent throughout all portions of the digestive system because of
`
`this varying pH range. One approach to solving this problem is disclosed in U.S.
`
`20
`
`Patent No. 5,202,128 to Angelo M. Morella, wherein is disclosed a pharmaceutical
`
`pellet composition having a core element including at least one highly soluble active
`
`ingredient and a core coating, which is partially soluble at a highly acidic pH. The
`
`pharmaceutical composition also includes a slow release of active ingredients at the
`
`acidic pH of the stomach and additionally provides a constant, relatively faster rate
`
`25
`
`of release of a pharmaceutical agent at the more alkaline pH of the intestine. This
`
`patent discloses a method and composition whereby the pellet composition is altered
`
`such that the polymers selectively included in the pellet composition have increased
`
`or decreased solubility based on the changes in pH within the biological system.
`
`However, this invention does not take into account those pharmaceutical agents
`
`30
`
`which are insoluble themselves at more basic pH levels. This patent appears to
`
`conclude that all pharmaceuticals are bioavailable even under basic conditions. The
`
`

`

`WO 99/66904
`
`PCT/US98/17120
`
`3
`
`disclosed invention therefore fails to solve the problem of affording solubility to
`
`those pharmaceutical agents which have pH dependent solubility.
`
`Additional attempts at pH independent release rates of drugs having a pH
`
`dependent solubility profile have been disclosed by a variety of approaches such as
`
`5
`
`the addition of an organic acid to a pellet formulation comprising a core made up of
`
`layers of the active agent and/or a salt thereof, and a polymeric material whereby the
`
`environment around the pellet becomes selectively acidic on a time release basis as
`
`disclosed in U.S. Patents 4,721,619; 4,826,688 and 4,863,742. Illustrative of organic
`
`acids that can be employed include acids such as adipic acid, ascorbic acid, citric
`
`10
`
`acid, fumaric acid, malic acid, succinic acid, tartaric acid and mixtures or
`
`combinations thereof. Disadvantages to this approach are stability of acid labile
`
`drugs while in the solid state in the pellet, stomach discomfort caused by the
`
`additional acid, and depletion of the added acid prior to complete dissolution and
`
`release of the drug.
`
`15
`
`An additional approach, which does not utilize organic acids, makes use of
`
`surfactants or wetting agents in the solid supports used for administration of these
`
`pharmaceutical agents, to increase solubility of the hydrophobic drug into the
`
`hydrophilic biological environment as disclosed in U.S. Patents 5,288,505 and
`
`5,529,791. The surfactants or wetting agents include fatty acid esters of saccharose
`
`20
`
`(commercialized under the trade names of SUCROESTERS and CRODESTERS),
`
`generically xylose esters or xylites, polyoxyethylenic glycerides, esters of fatty acids
`
`and polyoxyethylene sorbitan fatty acid esters, and polyglycides-glycerides as
`
`disclosed in U.S. Patent No. 5,288,505. However, the addition of such acids and/or
`
`surfactants may compromise the stability of certain drugs and/or may cause
`
`25
`
`processing problems due to the corrosive nature of the acids used. It would therefore
`
`be useful to achieve the pH independent bioavailability of a drug having a pH
`
`dependent solubility profile. It would furthermore be useful to achieve these goals
`
`without alteration of the ambient pH, or through the addition of surfactants to
`
`facilitate the assimilation of the hydrophobic drug in a hydrophilic biological
`
`30
`
`environment.
`
`

`

`WO 99/66904
`
`PCT/US98/17120
`
`4
`
`OBJECTS OF THE INVENTION
`
`It is therefore an object of this invention to provide for the controlled release
`
`of active pharmaceutical agents independent of ambient pH even though said agents
`
`have pH dependent solubilities.
`
`5
`
`It is another object of this invention to provide a drug delivery composition
`
`which avoids undesirable acid-drug interactions yet promotes the solvation of an
`
`acid soluble drug in an increasingly basic environment.
`
`It is a further object of this invention to provide a drug delivery composition
`
`which allows for solvation of an active drug which is soluble in an acid environment
`
`10
`
`but less soluble in a basic environment even though the ambient environmental pH
`
`progresses from acidic to basic pH.
`
`It is an additional object of this invention to provide a formulation whereby
`
`an acidic microenvironmental pH is maintained, facilitating the pH dependent
`
`solubility of the desired pharmaceutical agent, without necessitating an ambient
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`15
`
`alteration of pH.
`
`The above objects and others, which will become apparent in view of the
`
`following discussion and examples, are achieved by means of an extended release
`
`form of a pham1aceutically acceptable system which comprises a pellet formulation
`
`wherein the core of said pellet contains the drug and a latent acid which hydrolyzes
`
`20
`
`under mildly basic conditions creating an acidic microenvironment whereby the
`
`salvation of the active drug is achieved. Additionally, the pellet is coated with an
`
`outer rate controlling polymeric membrane.
`
`From the following summary it will also become apparent that the invention
`
`provides distinct advantages in campounding compositions of drugs having pH
`
`25
`
`dependent solubilities. The addition of a latent acid to the solid formulation will not
`
`change the overall pH and will therefore promote stability over similar formulations
`
`containing acids that might affect the stability of the acid labile drugs. Solid
`
`formulations not containing acids will prevent processing difficulties, such as
`
`corrosion, that might otherwise arise. Also, latent acids will protect against
`
`30
`
`interaction between the acid, drug and other constituents of the composition such as
`
`binders, diluents, and lubricants.
`
`

`

`WO 99/66904
`
`PCT/US98/l 7120
`
`5
`
`SUMMARY OF THE INVENTION
`
`Accordingly, this invention provides a coated pellet formulation which
`
`accomplishes the previously set forth goal of providing controlled release of an
`
`active drug wherein the release profile is pH independent even though the drug
`
`5
`
`solubility profile is pH dependent. This goal is accomplished through the
`
`incorporation of a latent acid, such as glucono delta-lactone or similar lactone,
`
`lactam, amide or ester, into the pellet or tablet formulation along with the drug. The
`
`selection of the latent acid portion of the formulation is dictated to some degree by
`
`the specific solubility characteristics of the pharmaceutical agent to be delivered and
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`10
`
`where along the digestive tract the drug is to be delivered. An ester based latent acid
`
`species would, for example, provide a better microenvironment for enhancing the
`
`delivery of a specific class of drug targeted for the lower GI tract where the pH is
`
`more basic, whereas the lactone based type of latent acid would be better suited to
`
`a class of drug which is to be delivered in the upper GI tract where the pl-I is more
`
`15
`
`neutral. The latent acid can be selected and formulated to hydrolyze at a desired pH.
`
`The latent acid used may be, for example, a member such as an amide, ester,
`
`anhydride, lactame and lactone of an organic acid. Each form of latent acid presents
`
`a range of pH within which it will undergo hydrolysis. Upon hydrolysis the latent
`
`acid acidifies the microenvironment within and immediately surrounding the pellet
`
`20
`
`or tablet. The microenvironmental acidification is sufficient to facilitate the
`
`salvation and release of the active drug even where the macroenvironmental
`
`surrounding pH is prejudicial to the drug's solubility. The prudent selection of the
`
`latent acid included in the formulation specifies the pH at which the latent acid will
`
`hydrolyze and at which the delivery of the active drug will commence. A polymeric
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`25
`
`coating is also applied to the pellet to control the drug release rate by facilitating
`
`hydrolysis of the latent acid at the appropriate macroenvironmental pH and
`
`solubilization of the drug. The coating material is both water and drug permeable.
`
`In this manner, the coating allows the migration of water into the tablet and the
`
`movement of latent acid/hydrolyzed acid and active drug out of the tablet. The
`
`30
`
`coating may also be selectively water soluble. Water solubility of the coating is
`
`useful, for example, where increased permeability is desired or where other
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`

`

`WO 99/66904
`
`PCT/US98/17120
`
`6
`
`requirements of the active drug so dictate. Selective and variable water solubility of
`
`the coating is predetermined by the chemical composition of the coating material.
`
`Increasing the thickness of the coating is one way that the coating solubility is
`
`altered. Thickness and composition of the coating will influence the rate of drug
`
`5
`
`release.
`
`Glucono delta-lactone, one specific example of a type of latent acid, offers
`
`various advantages over previously reported organic acids. Glucono delta-lactone
`
`is a neutral molecule since it is a lactone of gluconic acid possessing no acidic
`
`functional groups. In solid state, this molecule does not have an adverse affect on
`
`10
`
`drug stability, even for drugs that are acid labile. Likewise, because this formulation
`
`does not have a free acid grouping, the latent acid moiety does not interact with other
`
`components used in the formulation.
`
`Specifically, in vivo, at an appropriate pH, glucono delta-lactone will be
`
`hydrolyzed into gluconic acid, which acidifies the microenvironment within the
`
`15
`
`pellets, thereby solubilizing the drug, irrespective of the surrounding pH. From a
`
`chemical stability standpoint, the formulation contains a lactone, which is pH
`
`neutral, and does not change the pH of the formulation in solid state. However, the
`
`lactone behaves as a latent acid since, in the presence of an aqueous environment and
`
`at a more basic pH, it hydrolyzes into gluconic acid.
`
`20
`
`The kinetics of conversion of glucono delta-lactone to gluconic acid provides
`
`an added advantage to this approach.
`
`Initially, upon administration when the
`
`formulation is in the stomach, the drug solubility is high in the acidic gastric
`
`macroenvironment. By the time the formulation undergoes gastrointestinal transit
`
`and the pH slowly becomes more basic, the glucono delta-lactone is hydrolyzed into
`
`25
`
`gluconic acid. Through this hydrolysis, this latent acid form is converted into a free
`
`acid. The free acid is able to discharge its protons causing an acidification of the
`
`microenvironment. This mechanism allows the latent acid portion of the formulation
`
`to maintain the acidic microenvironmental pH within the pellet. Thus, by the time
`
`the formulation reaches the higher physiological pH of the intestine, which is
`
`30
`
`inimical to drug solubility of acid dependent soluble drugs, the lowering of the
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`

`

`WO99/66904
`
`PCT/US98/17120
`
`7
`
`microenvironmental pH is achieved by hydrolysis of the latent acid, thereby
`
`overcoming the pH dependent drug solubility problem.
`
`The maintenance of the pH within the solubility range of the drug in the
`
`microenvironment of the pellet formulation facilitates the absorption of the active
`
`5
`
`drug. This ability to alter the microenvironmental pH within and in the immediate
`
`environs of the pellet becomes increasingly important as the pellet traverses the
`
`alimentary canal from the stomach to the lower GI. The pH changes significantly
`
`between the stomach, where the pH is very acidic, to the lower GI, where the pH is
`
`more basic, e.g., in the region of pH 7 or even higher. For sustained drug delivery
`
`10
`
`along the lower alimentary tract it is important to deliver an active agent, which is
`
`only soluble under acidic pH, in a bioavailable form. A formulation which contains
`
`a latent acid facilitates this delivery because, under conditions which are more pH
`
`basic, the latent acid is hydrolyzed into the acid causing the microenvironmental pH
`
`of the pellet to become acidic. Thus, when the pellet formulation of the present
`
`15
`
`invention reaches the higher physiological pH of the intestinal tract, the desired
`
`microenvironmental acidic pH of the pellet is maintained and the drug is made
`
`bioavailable in soluble form.
`
`PREFERRED EMBODIMENTS
`
`20
`
`The following definitions will be helpful in defining terms used in this
`
`invention and will avoid repetitive explanation of terminology.
`
`The term "microenvironment," "microenvironmental," and the like shall mean
`
`the environment within and immediately surrounding the pellet or tablet. The
`
`environment within and immediately surrounding the pellet or tablet shall mean the
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`25
`
`inner portion of the pellet or tablet and the outer shell layer, including a limited area
`
`surrounding the pellet or tablet.
`
`The term "permeable polymer" and the like shall mean a polymer that is
`
`permeable to water, the latent acid, the hydrolyzed acid, and the active drug. This
`
`term includes bi-directional permeation such that simultaneous in-flux and out-flow
`
`30
`
`of any or all of these molecules occurs. The coating allows the movement of water,
`
`the latent acid, the hydrolyzed acid and the active drug out of the pellet or tablet.
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`

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`WO 99/66904
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`PCT/US98/17120
`
`8
`
`Likewise, the permeability of the coating allows for transfer of water into the core
`
`to cause the hydrolysis of the latent acid. Importantly, the core is equally permeable
`
`to the latent acid and to the hydrolyzed acid. This permeability is a property of the
`
`coating. Although the permeability of the coating can be altered because of partial
`
`5
`
`water solubility of the coating, the coating has the required permeability even where
`
`the coating is insoluble.
`
`The
`
`latent acid may be any composition which will adjust
`
`the
`
`microenvironmental pH to facilitate salvation of the active drug. The term "latent
`
`acid" preferably means any lactone, anhydride, amide, lactam, ester, and the like of
`
`10
`
`any organic acid that hydrolyzes into an organic acid at desired rate.
`
`The terms "drug," "active agent," "pharmaceutical," and the like shall mean
`
`any drug which is a base (in its galenical form or as its pharmaceutically acceptable
`
`salt), displaying pH dependent solubility (with higher solubility under acidic
`
`conditions and lower solubility under basic conditions). Such drugs include, but are
`
`15
`
`not limited to, verapamil, diltiazem, quinidine, propranolol, bromocriptine,
`
`chlorphenaramine, prochlorperazine, dextromethorphan, enalapril,
`
`labetalol,
`
`nicardipine, pentazocine, phenylpropanolamine, promethazine, diphenhydramine,
`
`metoclopramide, selegiline, timolol, trimethobenzamide, and albuterol, in their
`
`galenical form or as their pharmaceutically acceptable salts (such as hydrochloride,
`
`20
`
`sulfate, hydro bromide and phosphate salts).
`
`Various conventional tableting or pelleting agents such as binders, fillers,
`
`lubricants and the like may be included in the formation of the tablets or pellets
`
`containing the drug and latent acid. While such ingredients promote the functionality
`
`of the invention, they, by themselves, are not novel ingredients.
`
`25
`
`The term "binder" refers to an agent that contributes to the cohesiveness of
`
`the tablet or pellet and can be any ingredient conventionally used as such. Examples
`
`of suitable binders are polymers such as povidone, starch, natural gums,
`
`hydroxypropyl methyl cellulose or sucrose.
`
`The term "diluent" means an inert ingredient utilized as a carrier or as a
`
`30
`
`provider of bulk to the tablet or pellet. Exemplary of a suitable carrier is
`
`microcrystalline cellulose, due to its ability to be extruded and spheronised. The
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`

`

`WO 99/66904
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`PCT/US98/l 7120
`
`9
`
`inclusion of a diluent facilitates the fabrication of the tablet or pellet. Any other
`
`suitable diluents could be used provided they are functional in the extrusion and
`
`spheronization of the tablet or pellet.
`
`The term "lubricant" refers to any ingredient that enables the tablet or pellet
`
`5
`
`to be mechanically formed without adhering to the pelleting or coating machinery.
`
`Also, the lubricant shall mean additives that reduce pellet to pellet or tablet to tablet
`
`adherence concerns. Examples of lubricants are talc or magnesium stearate.
`
`Essential to the formation of the core or body of the tablets or pellets is the
`
`drug and latent acid. The drug to latent acid ratios may vary depending upon the
`
`10
`
`specific pH dependency or solubility characteristics of the drug, the strength of the
`
`latent acid, and the like. Generally, the weight ratio of the drug to latent acid may
`
`vary between about l :99 to 50: l with ratios of about 1: 10 to 5: l being preferred.
`
`Optimal ratios of drug to latent acid are about 2: I.
`
`The drug/latent acid will comprise between about 5 to 90% by weight of the
`
`15
`
`uncoated tablet or pellet. Preferably the inert ingredients such as binders, diluents,
`
`lubricants and the like will be present in amounts of between about l O to 95% by
`
`weight. In other words, the drug/latent acid will comprise between about 5 to 90%
`
`by weight of the tablet or pellet with amounts of between about 60 to 90% being
`
`preferred for high dose drugs, between 5 to 20% being preferred for low dose drugs,
`
`20
`
`and 20 to 60% being preferred for medium dose drugs. The remainder of the
`
`composition will be made up of the above mentioned inert ingredients.
`
`The core tablets or pellets are prepared by conventional techniques. For
`
`example, the dry ingredients can be combined in a blender followed by the addition
`
`of an appropriate amount of water or other suitable binding agent to form a wet mass
`
`25
`
`which is then extruded through a screen into plastic extrudates which are then
`
`processed into spherical tablets or pellets using a spheroniser. If certain ingredients,
`
`such as povidone, are to be added as a solution, the dry ingredients are first blended
`
`and then the additional ingredients are added as an aqueous solution and extruded
`
`by using wet extrusion followed by spheronisation and other techniques known in
`
`30
`
`the art. The tablets or pellets are then dried at elevated temperatures preparatory to
`
`being coated by a time release polymeric coating.
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`

`

`WO 99/66904
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`PCT/US98/17120
`
`10
`
`The polymeric coating is applied to the tablets or pellets in a single coating
`
`or multiplicity of coatings using conventional coating techniques. The coating is a
`
`polymer or mixture of polymers having varying degrees of hydrophilicity and/or
`
`hydrophobicity. It is the permeability profile of the coating that enables the entry of
`
`5
`
`water into the tablet or pellet. Likewise, the permeability profile of the coating
`
`facilitates the outward movement of both the acid and active drug into the
`
`macroenvironment. At the higher pH environment of the intestinal tract this influx
`
`of water at a basic pH causes the hydrolysis of the latent acid to its acid form,
`
`decreasing the microenvironmental pH and thereby solubilizing the drug that would
`
`10
`
`otherwise be insoluble in that environment. The solubilized drug is then released
`
`from the tablet or pellet through the coating into the macroenvironment of the
`
`digestive tract for absorption. Hence, it is the coating that controls the drug release
`
`rate secondary to the macroenvironmental pH controlling the hydrolysis of the latent
`
`acid that enables the solubility of the drug for release.
`
`15
`
`Polymeric coatings oflimited water solubility having increased solubility at
`
`higher pH ranges, as encountered in the small and large intestines, which are suitable
`
`for the pH independent release of drugs, are known in the art and are adequately
`
`disclosed in U.S. Patents 5,202,128; 5,330,766 and 5,378,474. No claim is made as
`
`to the discovery of any novel polymeric coatings, but rather claim is made to the
`
`20
`
`discovery that drugs, having acid dependent solubilities, may be rendered soluble
`
`independent of the macroenvironmental pH, by means of the incorporation of a
`
`latent acid into the tablet or pellet core which is then coated with a polymeric coating
`
`of selectable permeation, water solubility and which is preferably increasingly
`
`permeable at increasing pH ranges.
`
`25
`
`An equally viable mechanism of action of the present invention proceeds
`
`along similar pathways except that the delivery of the drng is not dependent upon the
`
`solvation of the drug within the confining of the tablet or pellet. It is within the
`
`scope of this invention for the drug to exit the tablet or pellet into the immediate
`
`exterior microenvironment, where, if the pH is acidic, the drug will be easily
`
`30
`
`dissolved and absorbed. However, as the pH rises, the latent acid will be hydrolyzed
`
`and cause a lowering of the microenvironmental pH in the surrounding tablet or
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`

`

`WO 99/66904
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`PCT/US98/17120
`
`11
`
`pellet microenvironment. This will in turn facilitate the salvation of the acid soluble
`
`drug with resultant increase in its release activity.
`
`For example, the polymers utilized may be hydrophobic polymers such as
`
`ethyl cellulose, with or without a hydrophilic polymer, such as hydroxypropyl
`
`5
`
`methyl cellulose, along with a plasticizer such as polyethylene glycol, polysorbate
`
`80, glycerol, and the like. Illustrative of such polymeric coatings are those marketed
`
`under the trade name SURELEASE and OPADRY (manufactured by Colorcon).
`
`SURELEASE is a formulated hydrophobic polymer suspension containing ethyl
`
`cellulose and a plasticizer. OP ADRY is a hydrophilic powder formulation
`
`10
`
`containing hydyoxypropyl methyl cellulose and a plasticizer.
`
`Aqueous coating suspensions of the above mentioned ethyl cellulose or
`
`combinations of ethyl cellulose and hydroxypropyl methyl cellulose, mixed in
`
`different proportions, have been successfully employed in making coated tablets or
`
`pellets. These coating compositions can range from 100% ethyl cellulose to a
`
`15
`
`mixture containing ethyl cellulose and hydroxy propyl cellulose in a variety of
`
`weight ratios such as 95:5, 90:10, 80:20, 75:25, 70:30, 60:40 or 50:50. This
`
`combination of a hydrophilic and hydrophobic polymers allows controlled
`
`designation of the water solubility of the tablet or pellet coating. The coatings can
`
`be formed from any combination of water soluble and water insoluble components
`
`20
`
`as long as the desired level of water solubility and coating film permeability is
`
`accomplished.
`
`Use of ethyl cellulose and hydroxy propyl methylcellulose is not restricted
`
`to the above mentioned products. For example, an ethyl cellulose manufactured by
`
`FMC Corporation under the trade name AQUACOAT may also be employed.
`
`25
`
`Other polymeric coatings may be utilized in the place of cellulosic polymers.
`
`For example, acrylic resins such as those sold by Creanova Inc. under the trade
`
`names EUDRAGITS RS, RL, and NE may also be used in the present invention,
`
`where these polymeric coatings are representative of coatings with hydrophobic,
`
`hydrophillic and neutral characteristics known in the art. These acrylic resins may
`
`30
`
`be combined in appropriate proportions to achieve the desired release rates and
`
`coating solubility. Plasticizers such as triethyl citrate, tributyl citrate, acetyl tributyl
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`

`

`WO 99/66904
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`PCT/US98/17120
`
`12
`
`citrate, and dibutyl sebacate may be added as a component to acrylic coatings as may
`
`a processing aid such as talc. Again reference is made to U.S. Patents 5,202,128;
`
`5,330,766 and 5,378,474 as representative of coatings that may be used to coat the
`
`acid labile drugs and latent acids which form the basic ingredients of the tablets or
`
`5
`
`pellets of the present invention.
`
`The tablets or pellets can be formulated such that each contains an effective
`
`unit dosage of the acid soluble drug or, in the alternative, a multiplicity of tablets or
`
`pellets may be required to achieve a unit dosage form. The drug/latent acid ratio
`
`within the tablet or pellet and coating of the tablet or pellet may be different for each
`
`10
`
`type of tablet or pellet in a dosage form if comprised of more than one type of tablet
`
`or pellet.
`
`EXAMPLES
`
`Specific examples showing the use of glucono-8-lactone as the latent acid
`
`· and the demonstration of pH independent release rates for drugs with pH dependent
`
`15
`
`solubilities are described below.
`
`EXAMPLE 1
`
`20
`
`25
`
`30
`
`A representative tablet or pellet formulation having the following
`
`composition was prepared as shown:
`
`Ingredients
`
`%w/w
`
`mg/dose
`
`Verapamil HCl
`
`Glucono-8-Lactone
`
`1Avicel PHIOI
`
`2Povidone K-29/32
`
`1microcrystalline cellulose
`2polyvinylpyrrolidone
`
`58
`
`29
`
`11
`
`2
`
`240
`
`120
`
`45.5
`
`8.3
`
`All the ingredients, except Povidone, were blended together as powders in
`
`the ratio shown above, and then transferred into a Hobart-type blender. The powder
`
`mixture was granulated by adding additional