throbber
Consommation
`et Corporations Canada
`
`Consumer and
`Corporate Affairs Canada(ll)
`
`(A)
`
`Bureau des brevets
`
`Patent Office
`
`Ottawa, Canada
`K1A OC9
`
`(22)
`
`(43)
`
`(52)
`
`2,004,565
`
`1989/11/28
`
`1990/05/31
`
`167-209
`
`5
`(51) INTL.CL. A61K-31/00
`
`(19) (CA) APPLICATION FOR CANADIAN PATENT (12)
`
`(54) Sustained Release Diltiazem Formulation
`
`;
`- U.S.A.
`(72) Chan~, Richard R.
`Pereira-Rosario, Ronald - U.S.A.
`Rudnic, Edward M.
`U.S.A.
`
`(73) Schering Corporation - U.S.A.
`
`;
`
`(30)
`
`(US) 278,057 1988/11/30
`
`(57) 12 Claims
`
`.1.-..:: .. _
`
`U1
`
`.. ....
`0 w
`..
`N
`.........
`0\
`
`""'
`
`Notice: The specification contained herein as filed
`
`Canada
`
`·, ~· .
`...
`"''
`
`··.··.
`
`·.· ... ·
`
`CCA 3254 (10·89) 41
`
`1
`
`EX 1007
`IPR of U.S. Pat. No. 7,829,595
`
`

`
`2004565
`
`ABSTRACT
`
`A sustained release diltiazem tablet is
`disclosed which exhibits a unique dissolution profile due
`in large me~sure to the inclusion of the drug into a
`hydrophobic matrix.
`In particular, the sustained release
`diltiazem formulation disclosed herein is suitable for
`once-a-day administration.
`
`. ;
`
`. .
`
`·~ .. ·
`
`2
`
`

`
`2004565
`
`2538K
`
`SUSTAINED RELEASE DILTIAZEM FORMULATION
`
`SUMMARY
`The present invention encompasses sustained
`release oral dosage forms and formulations for medicinal
`agents, and in particular for diltiazem.
`One such oral dosage form is a sustained
`release tablet, comprising an effective amount of active
`ingredient and excipients which may be compressed into a
`suitable oral dosage form, and which may be coat-ed with
`one or more coating- agents. The tablet coating may
`optionally contain diltiazem for immediate release.
`In a particular formulation described herein, a
`sustained release tablet may contain diltiazem or a
`pharmaceutically acceptable salt thereof in combination
`with excipients such as glyceryl monostearate, sucrose,
`microcrystalline cellulose and povidone.
`The matrix formed by tablet compression is
`hydrophobic in nature.
`
`BACKGROUND OF THE INVENTION
`Numerous references disclose diltiazem in
`sustained release formulations which utilize
`microencapsulation technology. Examples are the
`following:
`
`~ . .
`
`:~·
`
`3
`
`

`
`20IT4565
`
`U.S. Patent no. 4,452,042, issued to Samejima
`et al. on September 17, 1985;
`U.S. Patent no. 4,462,982, issued to Samejima
`et al. on July 31, 1984;
`U.S. Patent no. 4,443,497 issued ~o Samejima et
`al. on April i7, 1984; an~
`u.s. Patent 4,411,933, -issued to Samejima et
`al. on October 25, 1983.
`Similarly, numerous publications have disclosed
`devices which rely upon an osmotically regulated membrane
`for the controlled delivery of pharmaceuticals, such as
`diltiazem. For example are the following:
`Belgian Application 900817, published on
`February 1, 1985 discloses a device comprising a
`semipermeable wall, an osmopolymer, such as poly(ethylene
`oxide) and an active ingredient.
`Belgian Appl. No. 900,824 also published on
`February 1, 1985 discloses· a core and a membrane having
`variable permeab~lity;
`Belgian Appl. No. 898,819, published on May 30,
`1984, discloses a device for controlled drug delivery
`containing two compositions, including
`poly(ethyleneoxide);
`Belgian Appl. No. 903,540 published February
`17, 1986 discloses a sustained release powder, which can
`be formulated into an ointment, suspension etc.
`Belgian Appl. No. 901,359 published April 16,
`1985 discloses a controlled release diltiazem formulation
`containing granules and a semipermeable external
`membrane.
`
`Japanese Appl. No. 175,144 published on April
`13, ·1984, discloses a sustained release thermoset or,
`thermoplastic resin;
`Japanese Appl. No. 170,440 published on April
`5, 1984, discloses a sustained release tablet which
`utilizes hardened oil;
`
`4
`
`

`
`-·-
`;
`
`-3-
`2004565
`Japanese Kokai 62/5915, published January 12,
`1987, discloses diltiazem in combination with an acrylic
`acid resin;
`Japanese Kokai 61/212517, published September
`20, 1986 discloses the use of,diltiazem in combination
`-with hydrog~nated oils;
`Japanese Kokai 59/10512 published January 20,
`1984, discloses diltiazem microencapsulated in
`ethylcellulose;
`Panoz and Geohagan, U.S. Patent 4,721,619
`discloses an alternating arrangement (between 50 and 200
`layers) of diltiazem, organic acid and lubricant layers
`and polymeric material layers built upon a central inert
`core.
`
`However, none of the references disclose a
`sustained release diltiazem tablet formulation utilizing
`a uniformly dispersed hydrophobic matrix.
`
`DETAILED DESCRIPTION
`The present invention relates to a novel
`sustained release tablet, useful in that it exhibits
`unexpectedly prolonged activity, a uniform dissolution
`rate, and formulation stability over an extended period
`of time. The sustained release diltiazem tablets
`described herein will be suitable for once a day and
`twice daily administration.
`T
`The tablets of the invention utilize a
`hydrophobic matrix, into which the active ingredient is
`incorporated. As used herein, the term •hydrophobic
`matrix• refers to the nature of the major pharmaceu(cid:173)
`tically acceptable excipients into which the active
`ingredient such as diltiazem is incorporated prior to
`tableting. The components of the hydrophobic matrix are
`generally recognized as non-therapeutic, and are useful
`to impart the required dissolution characteristics to the
`sustained release tablets.
`
`5
`
`

`
`-4-
`~004565
`•Excipients• as used herein refers to non-
`. therapeutic ingredients which may be incorporated into
`the formulation. Hence, the components used to create
`the hydrophobic matrix are referred to as excipients.
`Other formulati~n excipients used in the manufacture of
`the sustained release diltiazem tablets include diluents,
`binders, fillers, glidants, lubricants, disintegrants,
`and other pharmaceutically acceptable non-therapeutic
`agents.
`
`A preferred sustained release tablet falling
`within the scope of the invention utilizes diltiazem
`hydrochloride or a solvate thereof as the active
`ingredient. Preferably the amount of the active
`ingredient, such as diltiazem, will be present at about
`20 to 500 mg per tablet, more preferably at about 30 to
`360 mg per tablet and most preferably at about 50 to 250
`mg per tablet, representing about 10 to about 40 percent,
`preferably about 10 to about 20 percent of the total
`tablet-weight.
`The diltiazem utilized herein also enco~passes
`other pharmaceutically acceptable acid addition salt
`forms thereof, as well as other pharmaceutically
`acceptable salts and esters thereof. As described above,
`the diltiazem used in Examples 1 to 7 below is the
`hydrochloride salt. Also included herein are
`stereospecific salt forms of diltiazem, both in pure form
`and racemic mixture. one such example is the (d,l)
`lactate form of diltiazem.
`The hydrophobic matrix utilized herein may be ·
`comprised largely of a mixture of mono- and diglycerides,
`e.g., glyceryl monostearate, and one or more of other
`known water insoluble excipients such as ethyl cellulose,
`cellulose acetate, calcium phosphate, cellulose acetate
`butyrate and microcrystalline cellulose. The hydrophobic
`matrix formed is generally non-water soluble, and serves
`to reduce the rate of dissolution.
`
`6
`
`

`
`-5-
`2001:1:565
`The pref erred hydrophobic matrix containinq
`qlyceryl monostearate (Atmul 84S, u.s. Emulsifier, Paris,
`IL) and microcrystalline cellulose (Avicel, FMC
`corporation) can contain relative portions of the two
`i~gredients ranging from apout 2:4 to about 4:2. The
`hydrophobic matrix therefore may form from about 40 to
`about 90 percent of the total tablet weight.
`Sugar, and in particular confectioner's sugar
`(size) 6 X can be used in the forrnul_ation described
`herein as a diluent. By increasing the concentration of
`sugar, an increased rate of dissolution will result. The
`diluent contained in the formulation can comprise from O
`to about 20 percent, being inversely rela~ed to the
`amount of hydrophobic matrix material present. For
`example, if a particularly long acting sustained release
`diltiazem tablet is desired, a larg~r amount of
`hydrophobic matrix material and a correspondingly low
`concentration of sugar is utilized.
`The tablet can utilize a conventional binder
`during the granulation step. Examples of binders are
`povidone, ethyl cellulose, acacia and a sugar solution,
`with povidone being preferred. The concentration of
`binder ranges from O to about 10 percent, preferably
`about 3 to about 10 percent, with the more preferred
`concentration being 4 to 5 percent.
`During preparation of the sustained release
`tablets, the diltiazem; hydrophobic matrix material,
`diluent (if present) and binder (if present) are mixed
`and then typically granulated. A lubricant is preferably
`added prior to tablet compression. Alternatively, a
`direct compression method, without employing a binder,
`may be performed. Typical lubricants are magnesium
`stearate, stearic acid, sodium stearyl fumarate,
`hydrogenated vegetable oil, calcium stearate, talcum and
`corn starch, with magnesium stearate being preferred.
`
`•,'
`
`7
`
`

`
`-6-
`2004565
`The lubricant, when present, may be added in an amount
`ranging from 0.5 to about 2 percent. The preferred
`amount of lubricant is about l percent of the total
`tablet weight.
`The granulation step can be performed using a
`back granulation technique, wherein the diltiazem,
`hydrophobic matrix materials, diluent and binder are
`combined. By adding part of the microcrystalline
`cellulose at the end, ~ess water is used to perform a wet
`granulation, thereby reducing drying time.
`The granulation technique, using the preferred
`ingredients described herein, and the back granulation
`technique described above, ~ay be performed by either (1)
`using a binder solution (wet method); or (2) using a
`solvent as a granulating agent and a binder in the dry
`form (dry method). However, the preferred granulation
`technique is the dry method. After granulation or mixing
`and after the addition of a lubricant, conventional
`tableting may be performed.
`Tablet cores., i.e., the tableted hydrophobic
`matrix, may be film coated if desired. The film coating
`may be non-functional to regulate drug release or may act
`as a barrier to delay release of diltiazem.
`Typical non-regulating coatings comprise water(cid:173)
`soluble agents applied using organic or, preferably,
`aqueous solvents using conventional spray technology.
`Such coatings provide tablets with increased hardness,
`better appearance, taste-masking and protection against
`light and moisture. Typical water-soluble coating agents
`are swellable hydrophilic polymers, and are selected
`based upon solubility, viscosity in solution, drying
`time, etc. Typical swellable hydrophilic polymers
`include cellulosic ethers such as hydroxypropyl
`methylcellulose, hydroxypropylcellulose, hydroxyethyl(cid:173)
`cellulose, and the sodium salt of carboxymethylcellulose,
`
`.·.,,
`
`8
`
`

`
`-7-
`2004565
`or mixtures thereof. When present, the amount of
`hydrophilic polymer comprises from about 0.5 to about 5\
`of the total tablet weight. An aqueous film coating
`procedure may be accomplished with or without a
`surfactant.
`A preferred non-regulatory coating includes
`hydroxypropyl methylcellulose (HPMC) USP 2910, more
`preferably an HPMC USP 2910 having a viscosity
`designation ES, and most preferably those sold under the
`trade name Methocel E5 Premium (Dow Chemical). The amount
`of HPMC ES-used, when present, comprises from about o.s
`to about 2 percent of the total tablet weight. Another
`coating mate~ial is HPMC USP 2910, more preferably an
`HPMC USP 2910 having viscosity designation ESO, and most
`preferably those sold under the trade name Methocel ESO
`Premium (Dow Chemical). The amount of HPMC E50 used,
`when present, similarly comprises from about 0.5 to 2
`percent of the total tablet weight.
`In the viscosity
`designations, •E• refers to USP 2910 and the number
`designa~ion refers to the viscosity in a 2% aqueous
`solution (i.e., ES has a viscosity of 5 cps and E50 has a
`viscosity of 50 cps).
`Where the tablet coating· is to act as a barrier
`to further regulate the release of diltiazem, water
`insoluble polymers and enteric polymers (i.e., water(cid:173)
`soluble at high pH) or combinations thereof can be used,
`again using conventional techniques. Examples of water(cid:173)
`insoluble polymers are ethyl cellulose, cellulose acetate
`butyrate, cellulose propionate and copolymers of acrylic
`and methacrylic acid esters. Examples of enteric polymer
`materials are cellulose acetate phthalate, cellulose
`acetate trimellitate, polyvinyl acetate phthalate and
`acrylic resins. The amount of water insoluble polymer,
`enteric polymer or combination thereof used, when
`present, comprises from about 0.5 to about 5% of the
`total tablet weight.
`
`·~:.·
`
`· .. ~
`
`. ·.:·
`
`9
`
`

`
`-a-
`2004565
`Other coating agents, such as plasticizers, may
`be included in either the water soluble or barrier
`coating solution. Examples of plasticizers are diethyl
`phthalate, dibutyl phthalate, triacetin, citric acid
`esters and polyethylene glycol, with polyethylene glycol
`3350 (wherein 3350 refers to the average mole~ular
`weight), also known as PEG 3350, being preferred. The
`plasticizer tends to make the film coat flexible, and may
`be included in an amount ranging from about 0.1 to 1
`percent of the total tablet weight.
`A liquid color dispersion such as a white color
`dispersion comprising mixture of propylene glycol,
`:povidone and titanium dioxide may be included in the
`coating step to impart a uniformly colored, finished
`appearance to the tablets. Such a mixture, when used,
`may comprise from about 0.5 to about 3 percent of the
`total tablet weight.
`Barrier films may also incorporate a water(cid:173)
`soluble channelling agent such as HPMC or another
`hydrophilic polymer identified above which will dissolve
`and create pores to facilitate dissolution.
`Alternatively, a water-insoluble but water-permeable
`polymer such as acrylic-methacrylic copolymer may be used
`to facilitate passage of water. Channeling agents, when
`present, are present in a concentration from about o.5 to
`about 2% of the total tablet weight.
`In another aspect of the invention, a portion
`of the diltiazem dose is incorporated into a water
`soluble binder and coated on the outside of the film(cid:173)
`coated tablet core to provide immediate release of a
`portion of the diltiazem, thereby minimizing some of the
`first pass effect of metabolism in the liver. The amount
`of diltiazem in the tablet core is from about 75% to
`about 95%, preferably about 90 to about 95% of the total
`amount of diltiazem present. Typical components and
`
`.· ..
`
`10
`
`

`
`-9-
`2004565
`concentrations of the water-soluble binder are as
`described above for the water-soluble tablet coatings.
`Typical tablet cores of the present invention
`therefore comprise the following ingredients in the
`following concentrations:
`a)
`10 to 40 percent_diltiazem hydrochloride;
`b)
`20 to 50 percent glyceryl monostearate;
`c) O to 20 percent confectioner's sugar;
`d)
`20 to 50 percent microcrystalline
`cellulose;
`e) o to 10 percent-povidone; and
`f)
`o to 2 percent magnesium stearate.
`
`Preferred ingredients and concentrations for the tablet
`cores are as follows:
`a)
`10 to 20 percent diltiazem hydrochloride;
`b)
`20 to 40 percent glyceryl monostearate;
`c) O to 20 percent confectioner's sugar;
`d)
`30 to 4~ percent microcrystalline
`cellulose;
`4 to 5 percent povidone; and
`e)
`f) o to 2 percent magnesium stearate.
`
`A preferred water-soluble coating is as follows:
`1 to 2 percent hydroxypropyl methylcellulose
`ES;
`1 to 2 percent hydroxypropyl methylcellulose
`E50;
`0.1 to 1 percent polyethylene glycol; and
`2 to 3 percent color dispersion.
`
`For.the diltiazem-containing coating, 1-2% diltiazem may
`be added to the above water-soluble coating. Percentages
`above are based on total final (i.e. coated) tablet
`weight.
`
`·
`
`•.,'·
`
`...
`
`11
`
`

`
`-10-
`2004565
`
`The following are specific examples of tablet
`formulations falling within the scope of the invention.
`However, the scope of the claims is not to be limited
`thereby.
`
`EXAMPLE 1
`
`Ingredient
`
`1. diltiazem HCl
`2. glyceryl monostearate
`3. confectioner's sugar 6X
`(N. F.)
`4. microcrystalline cellulose
`(N. F.)
`5. povidone (USP K-90)
`6. magnesium stearate
`7. hydroxypropyl methylcellulose
`(ES)
`8. hydroxypropyl methylcellulose
`(ESO)
`9. polyethylene glycol
`(NF M.W. 3350)
`10. color dispersion
`
`mg per
`tablet % (W/W)
`
`90.0
`160.8
`
`115.8
`
`244.2
`32.2
`6.4
`11.3
`
`8.6
`
`4.0
`
`16.7
`
`13.04
`23.30
`
`16.78
`
`35.39
`4.67
`0.93
`1.64
`
`1.25
`
`0.58
`
`2.42
`
`TOTAL:
`
`690.0
`
`100.0%
`
`Combine ingredients 1 through 4, or 1 through
`5, mix and granulate, using water in a back granulation
`technique. Add magnesium stearate, and compress with a
`conventional tableting procedure.
`Combine ingredients 7 to 10 using an aqueous
`solvent, and apply this film coating to the tablets if
`desired.
`
`The formulation described above in example 1
`has been tested for in vitro dissolution, bo~h in coated
`and 'uncoated form, and it demonstrates approximately 100
`percent dissolution over a 24 hour period, as
`demonstrated below in Table 1.
`
`, ...
`:.···,
`
`·.
`
`. : ..
`
`. , ... •
`
`.. -::
`
`.
`
`•
`
`•
`
`1
`
`12
`
`

`
`··.·
`
`.. · ..
`
`DISSOLUTION DATA FOR SUSTAINED RELEASE DILTIAZEM TABLETS
`
`TABLE I
`
`DESCRIPTION
`
`'
`
`1
`
`2
`
`4
`
`6
`
`8
`
`10
`
`12
`
`16
`
`20
`
`24
`
`HOURS
`
`'2ercent dissolution)
`
`Tablet of
`EXAMPLE 1,
`(Uncoated)
`
`29
`
`11
`
`31
`
`30.5
`
`45
`
`23
`
`44
`
`42
`
`68
`
`39
`
`61
`
`63
`
`ND
`
`49
`
`77
`
`88
`
`60
`
`83
`
`85
`
`ND
`
`72
`
`89
`
`92
`
`80
`
`92
`
`90
`
`97
`
`ND
`
`96
`
`ND
`
`97
`
`ND
`
`97
`
`ND
`
`98
`
`93
`
`98
`
`95
`
`Tablet of
`EXAMPLE. 1
`(Coated)
`
`25
`
`28
`
`20
`
`17
`
`.
`
`ND
`
`63
`
`82
`
`ND
`I
`54
`
`53
`
`ND
`
`87
`
`92
`
`ND
`
`72
`
`71
`
`79
`
`89
`
`93
`
`63
`
`62
`
`28
`
`43
`
`46
`
`28
`
`27
`
`43
`
`65
`
`70
`
`42
`
`41
`
`ND = NOT DETERMINED
`
`96
`
`90
`
`95
`
`98
`
`81
`
`80
`
`92
`
`ND
`
`ND
`
`ND
`
`101
`
`102
`
`ND
`
`ND
`
`ND
`
`ND
`
`ND
`
`101
`
`103
`
`95
`
`92
`
`N
`0
`0
`~
`CJ1
`~ c.n
`
`: ·.~
`
`-:-·
`
`13
`
`

`
`-12-
`2004565
`
`Examples 2 through 4 are further examples of
`pharmaceutical compositions that have been made by the
`methods described in Example l.
`
`EXAMPLE 2
`
`Ingredient
`
`mg/tablet
`
`1. diltiazem HCl
`2. glyceryl monostearate
`3. confectioner's sugar 6X (NF)
`4. microcrystalline cellulose (NF)
`5. povidone (USP K-90)
`6. magnesium stearate
`7. hydroxypropyl methylcellulose (ES)
`8. hydroxypropyl methylcellulose (E50)
`9. polyethylene glycol (NF M.W. 3350)
`10. color dispersion
`
`90.0
`276.6
`0
`244.2
`32.2
`6.4
`11.3
`· 8.6
`4.0
`16.7
`
`%
`(W/W)
`
`13.04
`40.08
`0
`35.39
`4.67
`0.93
`1.64
`1.25
`0.58
`2.42
`
`Total:
`
`EXAMPLE 3
`
`690.0
`
`100.0%
`
`Ingredient
`
`m9Ltablet
`
`1. diltiazem HCl
`2. glyceryl monostearate
`3. confectioner's sugar 6x (NF)
`4. microcrystalline cellulose (NF)
`5. povidone (USP K-90)
`6. magnesium stearate
`7. hydroxypropyl methylcellulose (E5)
`8. hydroxypropyl methylcellulose (E50)
`9. polyethylene Glycol (NF M.W. 3350)
`10. color dispersion
`
`90.0
`122.8
`30.1
`185.8
`21.1
`3.2
`7.9
`6.0
`2.8
`11.7
`
`%
`{WlW}
`
`18.69
`25.51
`6.26
`38.60
`4.39
`0.66
`1.64
`1.25
`0.58
`2.42
`
`Total:
`
`481.4
`
`100.0
`
`...
`
`14
`
`

`
`200~5{)5
`EXAMPLE 4
`
`Ingredient
`
`mg/tablet
`
`1. diltiazem HCl
`2. qlyceryl monostearate
`3. confectioner's sugar 6x (NF)
`4. microcrystalline Cellulose (NF)
`5. povidone USP
`6. magnesium Stearate
`7. hydroxypropyl methylcellulose (ES)
`8. hydroxypropyl methylcellulose (ESO)
`9. polyethylene g.lycol (NF·M.W. 3350)
`10. color dispersion (Solids)
`Total
`
`90.0
`155.6
`0
`183.1
`21.1
`3.2
`7.9
`6.0
`2.8
`11.7
`481.4
`
`' (W/W)
`
`18.69
`32.33
`0
`38.04
`4.39
`0.66
`1.64
`1.25
`0.58
`2.42
`100:0
`
`Pharmaceutical composi~ions as described in
`Examples 1-4 were also made which contained diltiazem in
`the amount of 120, 180 and 240 mg per tablet.
`
`EXAMPLE 5
`
`Ingredient
`
`mgltablet
`
`diltiazem HCl
`1.
`glyceryl monostearate
`2.
`3. microcrystalline cellulose, NF
`povidone USP
`4.
`s. magnesium stearate
`cellulose acetate phthalate
`6.
`diethyl phthalate
`7.
`
`180.0
`311.6
`366.6
`42.2
`6.4
`14.8
`3.7
`
`'
`
`{WlW~ -:-
`
`19.45
`33.68
`39.62
`4.56
`0.69
`1.60
`0.40
`
`Total:
`
`925.3
`
`100.00
`
`Prepare tablet cores from ingredients 1 through
`5 as.described in Example 1.
`Combine ingredients 6 and 7 in a
`pharmaceutically acceptable organic solvent(s) or alkali
`solution and coat the tablet cores using conventional
`techniques.
`
`i' ''
`
`.. :'·.·"
`
`. ·:
`
`· ..
`
`! ',.
`
`.,; .c:•
`
`.·.·:·
`
`15
`
`

`
`-14-
`2004565
`EXAMPLE 6
`
`Ingredient
`
`mg/tablet
`
`diltiazem HCl
`1.
`glyceryl monostearate
`2.
`3. microcrystalline cellulose, N.F.
`4.
`povidone USP
`5. magnesium stearate
`ethyl cellulose
`6.
`hydroxypropyl methyl cellulose
`7.
`- color dispersion
`8.
`
`180.0
`311.6
`366.6
`42.2
`6.4
`15.4
`7.0
`5.6
`
`' (W/W)
`
`19.26
`33.33
`39.22
`4.51
`0.68
`1.65
`0.75
`0.60
`
`Total:
`
`934.8
`
`100.00
`
`Prepare tablet cores from ingredients 1 though
`5 as described in Example 1.
`Combine ingredients 6 through 8 and coat
`tablets as described in Example 5.
`
`EXAMPLE 7
`
`Ingredient
`
`mg/tablet
`
`diltiazern HCl
`1.
`glyceryl monostearate
`2.
`rnicrocrystalline cellulose
`3.
`povidone USP
`4 •
`5. magnesium stearate
`6.
`cellulose acetate phthalate
`_7.
`diethyl phthalate
`8.
`diltiazem HCl
`9.
`hydroxypropyl methyl cellulose
`(E5)
`10. hydroxypropyl methyl cellulose
`(E50)
`11. polyethylene glycol (NF M.W. 3350)
`12. color dispersion
`
`166.0
`287.4
`338.1
`38.9
`5.9
`35.2
`8.8
`14.0
`9.1
`
`6.9
`
`3.1
`13.3
`
`' (W/W)
`
`17.91
`31.01
`36.48
`4.20
`0.64
`3.80
`0.95
`1.51
`0.98
`
`0.74
`
`0.34
`1.44
`
`Total:
`
`926.7
`
`100.00
`
`· .. ·.;:-_-::.·':
`...
`'
`
`,
`
`16
`
`

`
`-15-
`2004565
`Step A) Prepare tablet cores from ingredients
`1 though 5 as described in Example 1.
`Step B) Combine ingredients 6 and 7 and coat
`tablet cores from Step A as described in Example s.
`Step C) Combine ingredients 8 through 12 and
`coat tablets prepared in Step B as described in ~xample
`5.
`
`When the tablets are analyzed in terms of
`formulation stability for at least a 6 month period, the
`dissolution profile is virtually unchanged over ·an
`extended period of time.
`While Applicant has described what is believed
`to be the best mode for practicing the invention,
`numerous alternative embodiments are contemplated as
`falling within the scope of the invention described
`herein. Consequently, the scope of the claims is not to
`be limited thereby.
`
`.r~
`
`\':
`
`·· .. •
`
`17
`
`

`
`SUBSTITUTE
`
`REM PLACEMENT
`
`SECTION is not Present
`
`Cette Section est Absente
`
`....
`
`.
`
`. .
`.
`
`. '•
`
`.
`
`. . . · ..
`
`;
`
`·· ...... .
`
`.
`
`.
`
`. '
`
`..
`
`, . . .
`...
`. . . . . .
`.... '
`.
`
`...
`
`. ,_
`
`18
`
`

`
`r- ..
`
`-16-
`20045fi5
`The embodiments of the invention in which an exclusive
`property or privilege is claimed, are defined as follows:
`
`A sustained release diltiazem tablet comprising
`1.
`20 to 500 mg diltiazem or a pharmaceutically acceptable
`salt thereof in a hydrophobic matrix.
`
`A tablet as defined in claim 1 comprising 30 to
`2.
`360 mg diltiazem or a pharmaceutically acceptable salt
`thereof.
`
`A tablet as defined in claim 1 or 2 wherein the
`3.
`hydrophobic matrix comprises one or more of ethyl(cid:173)
`cellulose, a mixture of mono- and diglycerides, cellulose
`acetate, calcium phosphate, cellulose acetate butyrate
`and microcrystalline cellulose.
`
`A tablet as defined in claim 1, 2 or 3
`4.
`comprising a mixture of mono- and diglycerides in an
`amount of from about 20 to about 50 percent-of the total
`tablet weight.
`
`A tablet as defined in any of claims 2 to 4
`5.
`further comprising microcrystalline cellulose in an
`amount of from about 20 to about 50 percent of the total
`tablet weight.
`
`A tablet as defined in any of claims 1 to 5
`6.
`wherein the hydrophobic matrix further comprises a binder
`· in an amount of from about 3 to about 10 percent of the
`total tablet weight.
`
`A tablet as defined in claim 6 wherein the
`7.
`binder is povidone.
`
`:,:·
`
`19
`
`

`
`20045{)5
`
`-17-
`
`A tablet as defined in any of claims 1 to 7
`8.
`further comprising magnesium stearate in an amount of
`from about 0.5 to about 2 percent of the total tablet
`weight.
`
`A tablet a~ defined in any of claims 1 to 8
`9.
`further comprising a water-soluble or a barrier film
`coating wherein said coating comprises:
`a)
`in the case of a water-soluble coating, a
`swellable hydrophilic polymer in an amount of from about
`o. 5 to about 5 perce·nt of the total tablet weight; and in
`the case of a barrier coating, a water-insoluble :polymer,
`an enteric polymer or a mixture thereof, in an amount of
`from about 0.5 to about 5 percent of the total tablet
`weight, said barrier coating optionally comprising a
`channelling agent selected from a hydrophilic or water(cid:173)
`insoluble water-permeable polymer in an amount of from
`about o.s to about 2 percent;
`b)
`a plasticizer i-R an amount of from about
`6.1 to about 0.5 percent of the total tablet weight; and
`c) optionally, a color dispersion in an amount
`of from about 0.5 to about 3 percent of the total tablet
`weight.
`
`A tablet as defined in claim 9 wherein the
`10.
`water-soluble film coating comprises hydroxypropyl
`methylcellulose, polyethylene glycol 3350 and a color
`dispersion comprising propylene glycol, povidone and
`titanium dioxide.
`
`A tablet as defined in claim 9 wherein the
`11.
`barrier coating comprises one or more of diethyl,
`phthalate, cellulose acetate phthalate, ethyl cellulose,
`hydroxypropyl methylcellulose and a color dispension.
`
`20
`
`

`
`2QQ~565
`
`A tablet as defined in any of claims 1 to 11
`12.
`wherein up to 25% of the diltiazem in the tablet is
`present in a water-soluble film coating, wherein said
`water-soluble coating is as defined in claim 9.
`
`. :~
`
`. ·~
`
`. ·,·
`
`21

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