United States Patent [19]
`
`Rhodes
`
`\
`
`[11] Patent Number:
`[45] Date of Patent:
`
`4,880,830
`Nov. 14, 1989
`
`[54] SLOW RELEASE FORMULATION
`[75] Inventor: Alan Rhodes, Ely, United Kingdom
`[73] Assignee: Ethical Pharmaceuticals Limited,
`United Kingdom
`[21] Appl. No.: 12,026
`[22] Filed:
`Feb. 9, 1987
`[30]
`Foreign Application Priority Data
`Feb. 13, 1986 [GB] United Kingdom ............... .. 8603523
`
`[51] Int. Cl.4 ........................ .. A61K 9/16; A61K 9/26
`[52] U.S. c1. ...... .......................... .. 424/470; 514/965;
`424/468; 424/469; 424/472; 424/473
`[58] Field of Search ............. .. 424/468, 469, 470, 472,
`424/473; 514/965
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`
`
`
`
`2,809,916 10/1957 Hermelin 2,809,917 10/1957 Hermelin 3,148,124 9/1964 Gaunt ....... ..
`
`3,279,998 10/1966 116116161. ..
`3,400,197 9/1968 Lippmann ..
`
`3,402,240 9/1968 Cain etal. 3,870,790 3/1975 Lowey Ctal
`
`3,946,110 3/1976 11111 ....... ..
`3,962,414 6/1976 Michaels
`424/468
`4,369,172 1/1983 Schor et al.
`514/964
`4,540,566 9/1985 Davis et a1.
`424/469
`’ 4,590,062 5/ 1986 Jang ............. ,.
`.. 424/468
`4,695,467 9/1987 Uemura et a1.
`4,780,318 10/1988 Appelgren et al. ............... .. 514/965
`
`FOREIGN PATENT DOCUMENTS
`
`0013131 9/ 1980 European Pat. Off. .
`0094513 11/1983 European Pat. Off. .
`1021924 3/ 1966 United Kingdom .
`1033484 6/1966 United Kingdom .
`1137379 12/1968 United Kingdom .
`1333576 10/1973 United Kingdom .
`1405088 9/1975 United Kingdom .
`1486288 9/1977 United Kingdom .
`
`Primary Examiner-—-Ronald W. Griffin
`Attorney, Agent, or Firm-Saidman, Sterne, Kessler &
`Goldstein
`ABsTRAcr
`[57]
`A slow release formulation to be administered to hu
`mans or animals, comprising primary granules which
`contain an active ingredient and are in a secondary
`matrix of a water soluble/dispersible slow release mate
`rial, the granules themselves comprising particles con
`taining the active ingredients and in a primary matrix of
`a water soluble/dispersible slow release material.
`Optionally the formulation comprises a binder phase of
`a water insoluble slow release material having embed
`ded therein secondary granules comprising the second
`ary matrix containing the primary matrix granules.
`The water soluble/dispersible material may be a poly
`saccharide and acacia and low viscosity methylcellulose
`are exempli?ed, as well as alginate and gelatine.
`
`20 Claims, 4 Drawing Sheets
`
`acme/278M011 Mara?!
`
`@ 6944/1/14)?‘ 4w My
`
`Exhibit 1037
`ARGENTUM
`IPR2018-00080
`
`000001
`
`

`

`
`
`US. Patent—Nov. 14, 1989 Sheet 1 of 4 4,880,830
`
`
`
`AVG fF
`
`AMOIVE (INGREDIENT
`+
`
`BINDER BOLLIION
`
`
`
`%) AU
`
`AETIVE INGREDIENTBINDER MIXTURE
`
`2 GRANULATEAND DRY
`
`GRANULES.
`
`ouWETBINPERSOLUTION
`
`CRANE)BINDER MIXTURE
`
`|2 GRANLULATEAND DRY
`
`GRANULES
`
`DRY BLEND WITH
`WATER INBOLOBLE
`BINOER
`WAKSGRANOLE AGGLOMERATE
`
`
`
`@) 4055 7
`TABLE7S
`
`FAIBLETS
`
`000002
`
`000002
`
`

`

`US. Patent N0v.14, 1989
`Sheet 2 of4
`/767 Z
`
`4,880,830
`
`000003
`
`

`

`US. Patent Nov. 14, 1989
`
`Sheet 3 of 4
`
`4,880,830
`
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`
`US.Patent—Nov.14, 1989 Sheet 4 of 4 4,880,830
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`SLOW RELEASE
`THEOPHYLLINE PRELARATION
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`

`1
`
`SLOW RELEASE FORMULATION
`
`BACKGROUND OF THE INVENTION
`
`4,880,830
`
`30
`
`45
`
`_
`1. Field of the Invention
`The present invention relates to a slow release formu
`lation for pharmaceutical or veterinary use.
`2. Description of the prior art.
`The use of slow release formulations (also known as
`controlled release or sustained release formulatitons) is
`well established in medicine and the value of slow re
`‘lease formulations is widely appreciated. Slow release
`formulations have the advantage that the active com
`pound is released over a relatively long period so that
`the active compound is maintained in the blood stream
`for a longer time and at a more uniform concentration
`than would otherwise be the case. It is also known to
`formulate slow release preparations to release the active
`compound only when the preparation has reached a
`certain part of the digestive system.
`Many different proposals have been put forward for
`slow release formulations. One proposal for a slow
`release formulation is put forward in British Pat. No.
`1021924: in the process of this patent the medicament is
`admixed with a comrninuted sustained release material
`to obtain a dry mixture which is subsequently pressed
`into tablets. The sustained release material is said to be
`advantageously used in amounts of as much as 95%, a
`very high proportion indeed.
`It is also known to prepare slow release formulations
`by incorporating active ingredient in a water insoluble
`binder which will disperse only very slowly in the ali
`mentary system. For example, British Pat. No. 1137379
`discloses a multi-stage formulation process in which
`ethylcellulose (which is water insoluble) is used as
`35
`binder in the initial step. It would appear that in GB
`1137379 insufficient alcohol is used in the initial process
`ing to dissolve the ethylcellulose and thus a matrix (i.e.
`a uniform, continuous phase) is not formed. The process
`disclosed is very complex and would not be economi
`cal.
`Another controlled release formulation which uti
`lizes a water insoluble polymer is U.S. Pat. No
`3,962,414. The polymer of U.S. Pat. No. 3,962,414 is
`initially water soluble but is cross-linked with polyva
`lent metal cations in the ?nal formulations, and the
`patent discloses three different structures which use the
`cross-linked polymer to release drugs to the eye.
`British Pat. No. 1486288 describes a water insoluble
`matrix which holds an active substance (e.g. a drug). EP
`0094513 covers a device having not a water soluble
`matrix but a biodegradable one. The device is suitable
`for use as an implant, because the release of active mate
`rial has a duration of several months or more and is
`achieved by biodegradation of the polymers comprising
`the system.
`‘
`U.S. Pat. No. 2,809,916 discloses a formulation pro
`cess using repeated steps (processes using'9 to 15 steps
`are exempli?ed) of mixing a drug with water insoluble
`excipient, drying and granulating. At each granulation
`step the mix is granulated to the same size and the result
`of such a process is a uniform and intimate mixture of
`excipient and active ingredient. The reason for carrying
`out the multistage process is apparently that sufficient
`excipient could not be combined with the active ingre
`dient in one step - if all the excipient were added in one
`step the result would be an unworkable slurry. The US
`patent states that by increasing the number of mixing
`
`55
`
`60
`
`65
`
`2
`drying steps the rate of release of the drug is slowed but
`it is to be expected that when the amount of insoluble
`binder is increased in this way the rate of release will be
`slowed.
`A two stage formulation process is also disclosed in
`Example 8 of U.S. Pat. No. 3,946,110, in which aspirin
`powder is ?rst mixed with pectin, then granulated and
`mixed with potato starch and silica. The potato starch,
`however, acts not as a slow release binder but as a disin
`tegrator to accelerate release of aspirin. The inclusion of
`silica is for absorption of atmospheric moisture before
`this has a chance to react with the aspirin to form acetic
`and salicylic acids.
`I have now appreciated that there remains a need for
`an economical slow release formulation. In particular, it
`would be desirable to provide slow release formulations
`which need only include cheap and readily available
`excipients and which can be made using existing ma
`chinery.
`SUMMARY OF THE INVENTION
`I have now discovered that the rate of release of
`'active ingredient in water soluble/dispersible matrix
`material may be slowed by arranging the active ingredi
`25
`ent in a novel physical arrangement in the matrix mate
`rial.
`Accordingly, the present invention provides a slow
`release formulation to be administered to humans or
`animals which uses water soluble/dispersible binder or
`binders (which must inherently take time to dissolve or
`disperse) to control the release of the active ingredient.
`The formulation comprises secondary granules which
`comprise primary granules within a secondary matrix of
`a water soluble/dispersible slow release material, the
`primary granules themselves comprising particles com
`prising an active ingredient within a primary matrix of
`a water soluble/dispersible slow release material.
`Also included in the invention is a method of making
`slow release formulations. In the method, particles com
`prising an active ingredient are mixed together with a
`solution or dispersion of a water soluble/dispersible‘
`slow release material, to form an agglomerate and is
`granulated’. The resultant primary granules, after dry
`ing, are mixed together with a solution or dispersion of
`a water soluble/dispersible slow release material to
`form an agglomerate. The agglomerate is then granu
`lated to form secondary granules of a larger size than
`the primary granules and dried. The second granulation
`step is necessary to obtain a suitable dosage form for
`administration. The secondary granules as such could
`be used as the dosage form and could be administered
`by, for example sprinkling on food. More usually, how
`ever the second granulation step is necessary for further
`processing to form tablets or capsules for oral adminis~
`tration. Although oral dosage forms are preferred, it is
`envisaged that the secondary granules could be incor
`porated in suppositories or implants.
`.
`The slow release formulations of the invention may
`be called “multi-matrix formulations”, since they com
`prise at least a primary matrix of slow release material
`binding the particles containing the active ingredient to
`form primary granules and a secondary matrix of slow
`release material which binds the primary granules to
`gether. Surprisingly, we have found that a multi-matrix
`formulation releases the active ingredient over a sub
`stantially longer period than a single matrix formulation
`
`000006
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`

`

`10
`
`20
`
`35
`
`40
`
`4,880,830
`3
`1 containing the same proportions of active ingredient
`and slow release material.
`The slow release formulations of the invention may
`alternatively be de?ned as comprising particles which
`comprise an active ingredient and are arranged as clus
`ters of relatively densely packed particles dispersed in
`water soluble/dispersible matrix material. The matrix
`material at the clusters (i.e. the primary matrix) may be
`the same as or different to the matrix material between
`the clusters (i.e. the secondary matrix).
`The method of the invention is a “building up” pro
`cess in which, because the second granulating step pro
`duces larger granules than the ?rst step, there is built up
`the non-uniform or discontinuous multi-matrix struc
`ture. This method should be distinguished from the
`homogenising multi-stage granulation process of U.S.
`Pat. No. 2,809,916 in which each granulation is to the
`same size and there is no building up and a uniform
`structure is achieved which is continuous in the sense
`that there are no sharp changes in the pattern of medica
`ment dispersion.
`The invention is not restricted as to the active ingre
`dient and any one or more active ingredients may in
`principle be used. For example, the formulations may
`contain aminophylline, theophylline or another bron
`25
`chodilator, for the treatment of asthma or bronchitis.
`Alternatively, the active ingredient may, for example,
`be a tranquiliser, e. g. hydroxyzine, chlordiazepoxide or
`chlorpromazine hydrochloride. Other possible active
`ingredients are analgesics (e.g. morphine), antibiotics or
`antihypertensives (e.g. propranalol).
`The same or different slow release materials may be
`used in the different matrixes. The water soluble or
`water dispersible material of the matrixes may be any
`such material which can be used as a pharmaceutical or,
`appropriately, veterinary binder and which is slowly
`soluble in water and/or poorly wetted by water, e.g. a
`cellulose derivative, especially methylcellulose, or
`other polysaccharide. Another preferred water solu
`ble/dispersible binder is acacia (gum arabic), optionally
`in admixture with another binder, such as tragacanth,
`agar, sterculia or starch, for example. When in admix
`ture, the acacia generally forms substantially 50 wt %
`or more of the mixture. Some or all of the acacia may be
`replaced with apricot gum.
`Other preferred water soluble/dispersible binders are
`gelatine and alginates.
`The matrixes consist of water soluble and/or dispers
`ible materials which can thus be applied in an aqueous
`medium. In the case of active ingredients which might
`be adversely affected by water (e.g. would be suscepti
`ble to hydrolysis) it may be preferable to use a pharma
`ceutically acceptable organic solvent or dispersant, for
`example a lower alkanol, especially methanol, ethanol
`or isopropanol, or a haloalkane, especially chloroform
`or methylene chloride. Suitable mixtures may also be
`used, e.g. aqueous ethanol or methanol.
`Matrix material is used in the process in solution or
`dispersion to ensure thorough mixing with the admixed
`material and the formation of a homogeneous matrix
`structure.
`The secondary granules may be bound in a binder
`phase of a water insoluble slow release material. If a
`water insoluble slow release material is used to bind
`granulated double matrix composition, a lipid material
`as described in British Pat. No. 1021924 may be chosen
`to form the binder phase. We have found hydrogenated
`castor oil to be satisfactory but any other lipid material
`
`4
`referred to in GB 1021924 may be used, for example. As
`examples there may be mentioned mineral, vegetable or
`animal waxes, a C24—C6z ester of a C12—C31 fatty acid
`and C12—C31 fatty alcohol, a Clo-C22 fatty acid, a
`Clo-C22 fatty alcohol or a mono-, di- or triglycerol ester
`of a Clo-C22 fatty acid. Especially preferred are hydro
`genated castor oil, glyceryl mono- or disterate, 12
`hydroxystearyl alcohol and micro-crystalline wax. The
`reader is referred to GB 1021924 or its equivalent U.S.
`Pat. No. 3,279,998 for further information. U.S. Pat. No.
`3,279,998 is included herein by reference.
`In addition to the active ingredient and the slow
`release materials, the formulations of the invention may
`include other components in any portion of the formula
`tion, for example ?llers (e. g. lactose, bentonite, calcium
`phosphate, glycine, calcium carbonate, kaolin, sucrose),
`lubricants (e. g. boric acid, cacao oil, paraffin, polyethyl
`ene glycol, talc, stearates, stearic acid), preservatives
`(e.g. methyl or ethyl p-hydroxybenzoate), absorption
`promoters (e.g. glycerin mono-or di-medium sized al
`kanoates), antioxidants, ?avourings, edible colouring
`agents and stabilizing agents.
`The formulations of the invention may be formulated
`into forms for oral administration (e.g. tablets or cap
`sules) and may be for either medical or veterinary use.
`In the preparation of tablets or capsules, the secondary
`granules may be dispersed in a water insoluble binder
`phase as described above prior to being formed into
`tablets or capsules. If desired, the tablets or capsules
`may be enteric, ?lm or sugar coated. Instead of being
`formulated into oral dosage form, it would be feasible to
`process the formulations of the invention into supposi
`tories or implants, in which case the secondary granules
`would generally be embedded in a water insoluble
`binder phase.
`The proportions of the different ingredients are not
`critical but the sustained release material of the matrixes
`generally amounts to about 1 to about 50% by weight of
`the total solids of the matrix material and the particles
`containing the active ingredient. Preferably, the amount
`of the sustained release material of the matrixes is of
`from about 1.5 to about 15% by weight of the total
`solids of the matrix material and the particles containing
`the active ingredient. The particular amount ‘of sus
`tained release material chosen will vary from applica
`tion to application and can be determined by the skilled
`person for each case.
`The active ingredient or ingredients plus any diluents
`generally form from about 50 to about 99%, more usu
`ally from about 85 to about 98.5% by weight of the total
`solids of the matrixes and the particles containing the
`active ingredients.
`If the formulations include a water insoluble binder
`phase, this may constitute from about 1 to about 50% by
`weight of the total solids of the formulation, for exam
`ple, although in some instances higher quantities might
`be desirable. Preferably, the binder phase amounts to
`about 5 to about 25% by weight of the total solids.
`Other minor ingredients generally amount to a few
`percent of the total solids of the formulations, e. g. from
`about 0.5 to about 5% by weight.
`
`45
`
`50
`
`55
`
`60
`
`65
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`FIG. 1 is a flow chart illustrating a method of prepa
`ration of the formulations of the invention;
`FIG. 2 is a schematic illustration of a formulation
`prepared by the method illustrated in FIG. 1;
`
`000007
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`

`

`4,880,830
`5
`FIG. 3 is a graph comparing the dissolution of a for
`mulation of the invention with a single matrix formula
`tion prepared with the same ingredients in the same
`proportions;
`FIG. 4 is a graph of mean plasma theophylline con
`centration following administration to volunteers of an
`aminophylline formulation of the invention and a com
`parative single matrix formulation;
`'
`FIG. 5 is a graph illustrating the in?uence of double
`matrix processing of a theophylline/methyl cellulose
`formulation; and
`FIG. 6 is a graph of mean plasma theophylline con
`centration following administration to volunteers of a
`double matrix theophylline formulation of the invention
`and a comparative marketed slow release formulation
`manufactured in accordance with British Pat. No.
`1405088, which is included herein by reference.
`
`15
`
`6
`The above described process may be modi?ed in a
`number of ways, as will be apparent to the skilled per
`son. For example, when using methylcellulose as one or
`both matrixes it might be advantageous in steps 1 and
`/or 3 of FIG. 1 to, ?rstly, dry blend high viscosity
`methylcellulose and, respectively, the particles contain
`ing the active ingredient or the single matrix granules
`and subsequently to mix the dry blend with a solution of
`low viscosity cellulose. Alternatively, the slow release
`material of one or both matrixes could initially be dry
`blended with the particles containing the active ingredi
`ents or the single matrix granules and subsequently
`water or another liquid (e.g. ethanol) would then be
`added to the dry blend and mixed therewith.
`The water insoluble binder, instead of being dry
`blended with the double matrix granules could be added
`as a melt or in an organic solvent, for example ethanol.
`It is further contemplated that the process could be
`modi?ed to obtain triple matrix granules by repeating
`steps 3 and 4 of FIG. 1 after step 4. However, in this
`case in stage 2 the mixture would generally be granu
`lated more ?nely then would otherwise be the case, and
`the third granulation step would be to a larger granule
`size than the second granulation step.
`The following Examples illustrate the invention:
`
`20
`
`25
`
`DETAILED DESCRIPTION OF THE
`INVENTION.
`Turning to FIG. 1, in a preferred method of the in
`vention, a powder of the active ingredient is blended,
`for example in a conventional mixer, with an aqueous
`solution or dispersion of a water soluble or dispersible
`sustained release binder to form an agglomerate. The
`solution or dispersion is desirably~ relatively concen
`trated, for example a solution of 1 part by weight of
`acacia in l to 2 parts, preferably 1.25 to 1.8 parts, by
`weight of puri?ed water. The use of a concentrated
`solution makes handling and drying of the resultant
`mixture relatively easy.
`The wet agglomerate is then dried, for example on a
`?uid bed drier. A temperature of 35° C. to 60° C. is
`suitable for the drying. After being dried, the mixture is
`passed through a dry granulator of rlatively ?ne mesh
`aperture (e.g. 600 um to 250 um mesh aperture, prefera
`bly 500 to 355 um) and, if necessary, may be further
`dried.
`The single matrix granules now obtained are then
`subjected to the same procedure again. They are mixed
`with binder solution (often but not necessarily the same
`solution as used in the ?rst stage), dried and granulated
`(generally to 2 mm to 1 mm mesh aperture) to obtain
`secondary granules.
`Step 5 of FIG. 1 is optional and thus the secondary
`granules may now be directly compressed into tablets
`or encapsulated or they may be dry blended with a
`water insoluble binder (e.g. hydrogenated castor oil)
`and compressed in a tablet press. The tablets may sub
`sequentlty be coated, e.g. with an enteric coating. It will
`be seen that the whole process may be carried out using
`conventional apparatus. Of course, the secondary gran
`ules may be processed into a dosage form other than
`tablets or capsules.
`FIG. 2 is a schematic cross-section through a portion
`of a tablet obtained after step 6 of the process of FIG. 1.
`The tablet comprises a binder phase 5 of a water insolu
`ble binder in which there are embedded double matrix
`or secondary granules 6 containing the active ingredi
`ent. The secondary granules 6 themselves comprise
`single matrix or primary granules 1 in a secondary ma
`trix 2 of sustained release binder. In turn, the primary
`granules 1 comprise particles 3 containing the active
`ingredient in a primary matrix 4 of sustained release
`binder.
`If desired, the above described process may be modi
`?ed by adding to the formulation at an appropriate stage
`a ?ller or other additional component.
`
`30
`
`35
`
`EXAMPLE 1
`
`FORMULA
`
`First Mix
`Aminophylline
`Acacia
`Purified water
`Second Mix
`Acacia
`Puri?ed water
`Binder Phase
`Cutina HR
`(Hydrogenated castor oil)
`
`1000 g
`50 g
`75 ml
`
`50 g
`75 ml
`
`200 g
`
`Method
`(1) Add the 50 g acacia dissolved in 75 ml water to
`the aminophylline in a mixer (Baker Perkins) under
`conditions of 100 rpm main impeller. Increase the speed
`to 500 rpm main/ 1000 rpm side and mix for 5 minutes.
`Scrape down and mix for 5 minutes and scrape down
`again and mix for a further 5 minutes.
`(2) Discharge the formed granules, ?uid bed dry at
`40° C. for 5 minutes and granulate to 500 um mesh
`aperture size.
`(3) Granulate to 355 um mesh aperture size and ?uid
`bed dry for 5 minutes at 40° C.
`(4) Place the dried granules back into the mixer and
`mix in the second portion of acacia dissolved in water.
`(5) Granulate to 1.4 mm mesh aperture size, ?uid bed
`dry at 40° C. for 5 minutes, and repeat this procedure
`twice.
`(6) Blend in the Cutina and compress under power in
`a Manesty F3 tablet press.
`There were obtained 20 smooth white to light grey
`tablets free from pits or blemishes with a slightly dis
`cernable matrix structure.
`
`Dissolution in water
`
`Mean Amount dissolved in 1 hr =
`Mean Amount dissolved in 2 hr =
`Mean Amount dissolved in 3 hr =
`Mean Amount dissolved in 4 hr =
`
`48%
`69%
`85%
`94%
`
`45
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`50
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`55
`
`60
`
`65
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`000008
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`

`7
`-continued
`Dissolution in water
`
`Mean Amount dissolved in 5 hr =
`
`98%
`
`The dissolution rate obtained with tablets of the in
`vention was compared with conventional single matrix
`tablets prepared by the procedure given in the follow
`ing Comparative Example.
`Comparative Example
`
`FORMULA
`Aminophylline
`Acacia
`Puri?ed water
`Cutina HR
`
`100 g
`10 g
`15 ml
`20 g
`
`4,880,830
`8
`Utilising the above formula batch l was processed
`according to the double matrix procedure and batch 2
`was processed by a single matrix procedure. Both
`batches utilised a solution of the methyl cellulose in
`water and both were processed to a final granule size of
`1.4 mm prior to dry blending with the lubricants (talc
`and magnesium stearate) and compression to 400 mg
`anhydrous theophylline tablets.
`On testing for dissolution in degassed, distilled water
`at 37° C. using the USP ‘Paddle’ procedure, at 100 rpm
`mixing speed, the two batches gave the following re
`sults.
`
`15
`
`% in solution
`
`Method
`The acacia in water was mixed with the aminophyl
`line using a mortar and pestle before drying and granu
`lating to form a 1.4 mm mesh aperture size granule. The
`Cutina was then dry blended and the product com
`pressed under power on a Manesty F3 tablet press.
`Dissolution
`
`20
`
`25
`
`Mean Amount dissolved in 1 hr =
`Mean Amount dissolved in 2 hr =
`
`70%
`97%
`
`30
`
`35
`
`The use of a single as opposed to double matrix of
`acacia for the aminophylline granules has resulted in an
`unexpectedly drastic increase in the rate of tablet disso
`lution as best demonstrated by FIG. 3, which is a graph
`of the dissolution rates of the tablets obtained in Exam
`ple l and those obtained in the Comparative Example.
`In vivo study of the tablets obtained in accordance
`with the general method of Example 1
`A study was undertaken in 4 healthy young volun
`teers wherein on each of 2 separate occasions, separated
`by at least a seven day washout period to permit “wash
`ing ou ” of aminophylline from the volunteers, each
`subject was administered either a 225 mg aminophylline
`tablet prepared using a method like that of Example 1,
`or a commercially available 225 mg slow release ami
`nophylline tablet formulated in accordance with British
`Pat. No. 1405088. Blood samples were obtained on
`administration of each test preparation and at suitable
`time intervals thereafter and subsequently analysed for
`50
`plasma theophylline concentration (the active moiety of
`aminophylline). FIG. 4 shows the mean plasma theoph
`ylline concentration versus time pro?les obtained. As
`can be seen the tablets produced according to the pres
`ent invention result in plasma theophylline concentra
`tions similar to those obtained by the marketted slow
`release aminophylline preparation.
`Example 2
`
`45
`
`Formula
`Theophylline Monohydrate
`Methyl Cellulose
`(low viscosity)
`Puri?ed Water
`Talc
`Mg. stearate
`
`Amount
`1100 g
`20 g
`
`450 ml
`
`60
`
`65
`
`Time (hrs.)
`1
`2
`3
`4
`5
`6
`7
`8
`
`Batch 1
`(Double Matrix)
`17
`24
`31
`37
`41
`47
`51
`55
`
`Batch 2
`(Single Matrix)
`20
`32
`44
`54
`64
`72
`80
`89
`
`These results are further presented graphically in
`FIG. 5 where the difference in rates of dissolution of the
`two preparations becomes very apparent.
`Again the double matrix formulation (Batch 1) was
`used in a bioavailability study (4 subjects), the results of
`which are shown in FIG. 6 in comparison to a single
`dose of 2>< 200 mg tablets of the reference slow release
`theophylline preparation. As before tablets prepared
`according to the present invention produced very simi
`lar results to those obtained with the reference mar
`keted slow release theophylline tablets.
`
`EXAMPLE 3
`The use of sodium alginate as the matrix material is
`shown in this Example.
`
`Formula
`Theophylline Monohydrate
`Sodium Alginate
`95% Ethanol
`Puri?ed Water
`Magnesium Stearate
`
`Amount
`550 g
`10 g
`20 ml
`250 ml
`5.6 g
`
`In the above formula the ethanol is present as a dis
`persant for the sodium alginate to enable thorough dis
`solution in the aqueous granulating medium. Batches 3
`and 4 were respectively processed by the single and
`double matrix procedures using the above formula.
`Finished tablets from the 2 batches were assessed for
`dissolution rate by the USP ‘Paddle’ procedure; de
`gassed distilled water@ 37° C.; 100 rpm paddle speed to
`yield the following data:
`
`Time (hrs)
`1
`2
`3
`
`% in solution
`
`Batch 3
`(Single Matrix)
`44
`76
`94
`
`Batch 4
`(Double Matrix)
`34
`61
`87
`
`000009
`
`

`

`EXAMPLE 4
`Gelatine may also be used as the matrix former as
`shown by this Example:
`
`5
`
`Formula
`Theophylline Monohydrate
`Gelatine
`Puri?ed Water
`Magnesium Stearate
`
`Amount
`550 g
`25 g
`125 ml
`5.75 g
`
`This particular formulation is processed by initially
`dissolving the gelatine in hot water. Processing may
`then be continued as previously described. In this Ex
`ample the batches produced were 5 (single matrix) and
`6 (double matrix) which on dissolution testing (condi
`tions as in Example 3) produced the following results:
`
`15
`
`Time (hrs)
`1
`2
`
`% in solution
`
`Batch 5
`(Single Matrix)
`58
`91
`
`Batch 6
`(Double Matrix)
`51
`83
`
`25
`
`40
`
`4,880,830
`10
`Again the slowing of dissolution when tablets are
`of a water soluble/dispersible slow release material in
`processed by the double as opposed to single matrix
`which said granules are dispersed.
`method is readily apparent.
`2. A slow release formulation as claimed in claim 1
`wherein both matrixes are formed of the same slow
`release material.
`3. A slow release formulation as claimed in claim 1
`wherein said slow release material of at least one of said
`matrixes is selected from the group consisting of poly
`saccharide material, alginate and gelatine.
`4. A slow release formulation as claimed in claim 3
`wherein said polysaccharide material is selected from
`the group consisting of acacia, a mixture comprising at
`least 50 wt % acacia and another binder, and low vis
`cosity methylcellulose.
`5. A slow release formulation as claimed in claim 1
`wherein said secondary matrix/ granule composition is
`itself in the form of granules and is in a binder phase of
`a water insoluble slow release material.
`6. A slow release formulation as claimed in claim 3
`wherein said secondary matrix/ granule composition is
`itself in the form of granules and is in a binder phase of
`a water insoluble slow release material.
`7. A slow release formulation as claimed in claim 6
`wherein said water insoluble slow release material is
`selected from the group consisting of mineral, vegetable
`or animal wax, C24-C62 esters of a C12-C31 fatty acid
`and C12—C31 fatty alcohol, Clo-C22 fatty acids, Clo-C22
`fatty alcohols, mono-, di- and triglyceryl esters formed
`from a Clo-C22 fatty acid, and mixtures thereof.
`8. A slow release formulation as claimed in claim 7
`wherein said water insoluble slow release material is
`selected from the group consisting of hydrogenated
`castor oil, glyceryl mono- and distearate, l2-hydroxys
`tearyl alcohol, micro-crystalline wax and mixtures
`thereof.
`9. A slow release formulation as claimed in claim 3
`and formulated for oral administration.
`10. A method of making a slow release formulation to
`be administered to humans or animals, comprising mix
`ing particles comprising an active ingredient and a solu
`tion or dispersion in a liquid vehicle of a water soluble/—
`dispersible slow release material to form an agglomerate
`and granulating said agglomerate to form primary gran
`ules, drying said primary granules and then mixing them
`with a solution or dispersion in a liquid vehicle of a
`water soluble/dispersible slow release material to form
`an agglomerate and granulating said agglomerate to
`form secondary granules of a larger size than said pri
`mary granules, and drying said secondary granules.
`11. A method as claimed in claim 10 wherein each
`said liquid vehicle is independently selected from the
`group consisting of water, ethanol, methanol, aqueous
`ethanol, aqueous methanol, chloroform, isopropanol
`and methylene chloride.
`12. A method as claimed in claim 10 in which the or
`each water soluble/dispersible material is selected from
`the group consisting of polysaccharide material, algi
`nate and gelatine.
`13. A method as claimed in claim 10 wherein there
`are two granulating steps and in the ?rst granulating
`step said agglomerate is granulated to a size of 600 um
`to 250 um mesh aperture and in the second granulating
`step said agglomerate is granulated to a size of 2 mm to
`1 mm mesh aperture.
`14. A method as claimed in claim 10 wherein said
`particles containing active ingredient or said primary
`granules or both are dry blended with high viscosity
`
`Again the double matrix formulation is seen to exhibit
`a more prolonged dissolution pro?le than the single
`matrix preparation. However, it is also apparent from
`all the examples that dissolution rate is also dependant
`on the type as well as amount of the matrix materials
`used. It is therefore apparent that the invention provides
`35
`scope for the production of slow release preparations of
`widely differing speci?cations so that the exact pro?le
`requi