United States Patent [19]
`Panoz et al.
`
`[11] Patent Number:
`[45] Date of Patent:
`
`5,051,262
`Sep. 24, 1991
`
`[54] PROCESSES FOR THE PREPARATION OF
`DELAYED ACTION AND PROGRAMMED
`RELEASE PHARMACEUTICAL FORMS AND
`MEDICAMENTS OBTAINED THEREBY
`[75] Inventors: Donald Panoz, Tuckerstown,
`Bermuda; Gilbert Corneille, Paris,
`France
`[73] Assignee: Elan Corp., P.L.C., Monksland,
`Ireland
`
`[21] Appl. No.: 933,287 ‘
`[22] Filed:
`Nov. 18, 1986
`
`[63]
`
`Related U.S. Application Data
`Continuation of Ser. No. 559,431, Dec. 8, 1983, aban
`doned, which is a continuation~in-part of Ser. No.
`287,722, Jul. 24, 1981, abandoned.
`Foreign Application Priority Data
`[30]
`Dec. 7, 1979 [FR]
`France .............................. .. 79 30085
`
`[51] Int. Cl.5 ....................... .. A61K 9/22; A61K 9/26;
`A61K 9/ 16
`[52] U.S. c1. .................................. .. 424/468; 424/469;
`424/489
`[58] Field of Search ...................... .. 424/468, 469, 489
`
`[56]
`
`References Cited
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`Primary Examiner-Frederick E. Waddell
`Attorney, Agent, or Firm—Robert H. Falk; Henry
`Croskell; Harry J. Watson
`
`ABSTRACT
`[57] _
`Speci?cally, the present invention relates to processes
`for preparing delayed action galenic forms. The process
`is characterized in that the application solutions of ex
`cipients, coatings and active constituents are adjusted to
`a desired pH. The independence of the rate of dissolu
`tion of a controlled release or sustained action oral
`pharmaceutical form is increased by admixing a pH
`adjusting agent with every application solution of medi
`cament, excipeint or coating, throughout the course of
`formulation of the pharmaceutical form.
`
`16 Claims, 10 Drawing Sheets
`
`

`
`Arch.
`
`Int.
`
`Pharmacodyn,
`
`5,051,262
`Page 2
`
`'
`
`US. PATENT DOCUMENTS
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`

`
`5,051,262
`
`Page 3 _
`
`OTHER PUBLICATIONS
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`of the Active Prinicples From Acrylic Polymer-Based
`Capsules”, pp. 7-17.
`’
`Brunnengraeber, Chem. Abstr. 76 #27955W-Drug
`Filled Capsules.
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`Preparations for Prophylactic and Therapeutic Treat
`ment of Coronory Heart Disease”
`Dittgen, Chem. Abstr. 85 #l98123p “Preparation and
`In Vitro Testing of Polyacrylate-Based Bead-Polymeri
`zates Containing Pharmaceutically Active Ingredi
`ents”.
`Dittgen, Chem. Abstr. 87 #l89376n “Preparation an In
`Vitro Testing of Polyacrylate-Based Polymers Con
`taining .
`. .”
`Dittgen, “Poliakrilat alapu gyogryszerhatoanyag-tar
`talmu gyongy-polimerizatumok eloallitasa es in vitro
`vizsgalata”, 20. evfolyam 7 szam.
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`plex Compound”.
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`Galeazzi, Chem. Abstr. 88 #1l845x “The Effect of an
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`Buchanan, Chem. Abstr. 88 #146l79d “Assessment of
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`zation of Indomethacin”.
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`7
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`bility of Indomethacin. Study of a Delayed-Release
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`
`

`
`US. Patent
`
`Sep. 24, 1991
`
`Sheet 1 of 10
`
`5,051,262
`
`
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`DISSOLUTION (96)
`
`DISSOLUTION (%)
`
`

`
`U.S. Patent
`
`Sep. 24, 1991
`
`Sheet 2 of 10
`
`5,051,262
`
`
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`
`U.S. Patent
`
`Sep. 24, 1991
`
`Sheet 3 of 10
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`5,051,262
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`
`US. Patent
`
`Sep. 24, 1991
`
`Sheet 5 of 10
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`5,051,262
`
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`

`
`US. Patent
`
`Sep. 24, 1991
`
`Sheet 6 of 10
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`US. Patent
`
`Sep.24,l991
`
`Sheet7 of10
`
`5,051,262
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`
`5,051,262
`
`
`
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`US. Patent
`
`sip. 24, 1991
`
`Sheet 8 of 10
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`

`
`U.S. Patent
`
`Sep. 24, 1991
`
`Sheet 9 of 10
`
`5,051,262
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`

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`US. Patent
`
`S'ép. 24, 1991
`
`Sheet 10 of 10
`
`5,051,262
`
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`DISSOLUTION (‘36)
`
`

`
`1
`
`PROCESSES FOR THE PREPARATION OF
`DELAYED ACTION AND PROGRAMMED
`RELEASE PHARMACEUTICAL FORMS AND
`MEDICAMENTS OBTAINED THEREBY
`
`CROSS-REFERENCED RELATED
`APPLICATIONS
`The present application is a continuation of US Ser.
`No. 559,431, ?led Dec. 8, 1983, which is a continuation
`of US Ser. No. 287,722, having a U.S. ?ling date of
`July 24, 1981, now abandoned, with a PCT interna
`tional ?ling date of Dec. 5, 1980, the entire contents of
`which are hereby incorporated by reference.
`
`5
`
`5,051,262
`2
`Until now, the addition of application solutions of
`excipients and of coatings, constituted by polyvinylpyr
`rolidone, gum-lacquer, waxes, syrups, etc., has been
`used as a means for moistening the pellets or tablets of
`sugar or the pellets and/or the tablets of active principle
`to cause the adherence thereto of subsequent layers of
`active component. It is precisely by the modi?cation of
`these application solutions that the object envisaged by
`Applicant has been obtained.
`To overcome this drawback, it has been known to
`add a solid pH adjusting compound to the active com
`ponent in an attempt to adjust the pH around the medi
`cament and improve the release of the active principle.
`However, except in the case of granules obtained by
`high compression (see British patent 2,039,737), this
`solid product does not exert its action completely in
`vivo since the dissolution into the stomach is not always
`complete and steady so that the drug is already ab
`sorbed through the gastro-intestinal tract when the
`optimum pH is ?nally attained in the stomach.
`
`‘ FIELD OF THE INVENTION
`The process is characterized in that the application
`solutions of excipients, coatings and active constituents
`are adjusted to a desired pH. Likewise, the present
`invention relates to improvements in or processes for
`the preparation of various pharmaceutical forms of
`medicaments with delayed action, and particularly, to
`processes for the preparation of tablets, granules, and
`the like, with delayed action and programmed release.
`
`25
`
`BACKGROUND OF THE INVENTION
`Much progress has been made in recent years in the
`preparation of forms for oral administration of medica
`ments with a view toward better control of the kinetics
`of release of medicament. Coating materials have been
`developed, as have manners to retain the medicament in
`inert matrices and manners for diffusion or controlled
`dialysis of medicaments. Recourse has even been had to
`the combination of several of these forms to ensure,
`starting from the same pharmaceutical form, a modi?ca
`tion of the absorption or of the elimination of the medi
`caments in order to prolong the time of action thereof,
`as in the case, for example, of the association in the same
`medicament of viscosifying agents which retard the
`dissolving process with active constituents of well de
`termined granulometry. The improvements which have
`been introduced in the preparation of pharmaceutical
`forms for oral administration with a prolonged action,
`are manifested principally (l) in a fractionation in the
`same medicament unit (capsule, tablet, granule) of the
`total dose into several small doses coated with suitable
`excipients which are made available to the organism at
`the desired time, (2) in the retention of the medicament
`in a sort of inert matrix which is very slowly splittable,
`in a form which is called upon to diffuse its contents
`gradually according to predetermined kinetics, and (3)
`in the ?xing of the medicaments to several adjuvants so
`as to obtain insoluble complexes from which the medi
`caments are eluted slowly and supplied to the organism
`according to predetermined kinetics.
`The various coatings and coating ?lms depend evi
`dently on the physiological factors (enzymatic activity,
`pH, etc.) which exist in the gastro-intestinal tract; these
`factors (and more particularly, the pH) vary not only
`throughout the gastro-intestinal tract, but also from one
`person to another. The possibility of controlling the
`release of the active principle throughout the course of
`the medicament in the gastro-intestinal tract assumes
`the ?rst place that it is possible to control the solubility
`65
`of the medicament at each moment of this process. The
`solubility of the majority of medicaments (if not all)
`varies precisely as a function of the pH.
`
`45
`
`60
`
`SUMMARY OF THE INVENTION
`It is accordingly an object of the present invention to
`further improve the process of the preparation of phar
`maceutical forms for oral administration of medica
`ments with prolonged action and programmable kinet
`ics.
`It is a further object of the present invention to pro
`vide a process for the preparation of such forms of '
`administration so as to be able to dispense with high
`compression.
`It is yet another object of the present invention to
`provide a process for the preparation of such forms of
`administration which reduces the cost price of these
`extremely widespread pharmaceutical forms.
`It is yet another object of the present invention to
`provide forms of medicaments for oral administration in
`which the solubility of the medicament is maintained
`substantially constant regardless of the pH of the partic
`ular portion of the gastro-intestinal tract through which
`the medicament is moving at any given point in time.
`It is also an object of the invention to provide novel
`galenic forms obtained according to the process of the
`present invention.
`The results obtained are spectacular both from the
`point of view of kinetics of release of the active sub
`stance, which are, besides, bound together.
`It is another object of the present invention to pro
`vide a medicament for oral administration which will
`provide an improved blood level pro?le of the medica
`ment with time.
`Yet another object of the present invention is to pro
`vide a pharmaceutical form for medicaments for oral
`administration in which acid unstable drugs are pro
`tected from acid hydrolysis in the stomach.
`These and other objects in accordance with the pres
`ent invention are obtained by creating a micro-environ
`ment surrounding the medicament throughout its
`course in the gastro-intestinal tract which will permit
`optimum solubility regardless of the pH of the portion
`of the tract in which the medicament is passing. Such a
`micro-environment is obtained by adding an appropri
`ate pH-adjusting agent to every layer of medicament,
`and preferably to every application solution and coating
`applied to the dosage form.
`Accordingly, a chief embodiment of our invention is
`directed to a process for the preparation of delayed
`action galenic forms, wherein the forms, wherein the
`
`

`
`5,051,262
`'3
`solutions for applying excipients, coatings and active
`constituents are adjusted to a desired pH. Further the
`invention is directed to the same process, wherein the
`application solutions are adjusted either depending on
`the medicament chosen, (1) to an alkaline pH by means
`of organic and/or inorganic bases and/0r basic salts, or
`(2) to an acid pH by means of organic acids and/or acid
`salts. Still further, an embodiment of our invention is
`directed toward galenic forms obtained according to
`_ the processes described in this chief embodiment.
`
`25
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`The present invention will be better understood from -
`a consideration of the following description of pre
`ferred embodiments and the appended drawings, in
`which:
`- FIG. 1 is a graph showing dissolution rates in curves
`plotting the percentage dissolution against time after
`administering at each pH of 1.5, 3.0, 6.0 and 7.5, for the
`product of Example 1.
`-
`FIG. 2 is a graph as in FIG. 1 for the product of
`Example 2.
`‘
`FIG. 3 is a graph as in FIG. 1 for the product of
`Example 3.
`FIG. 4 is a graph having curves comprising plasma
`levels of drug as a function of time after administration
`as a mean of the total subjects tested for the product of
`Example 1 and for the product of Example 3.
`FIG. 5 is a graph as in FIG. 4 with curves comprising
`plasma levels as a function of time for the product of
`Example 2 with those for the product of Example 3.
`FIG. 6 is a graph showing dissolution rates in curves
`plotting the percentage dissolution against time after
`administration of each pH of 1.5, 3.0 and 7.5, for ‘the
`product of Example 4.
`FIG. 7 is a graph as in FIG. 6 for the product of
`Example 2.
`FIG. 8 is a graph having curves comprising plasma
`levels of drug as a function of time as a mean ofthe total
`subjects tested for the product of Example 4 and for the
`product of Example 5.
`FIG. 9 is a graph having curves showing plasma
`levels of drug as a function of time for each of the
`twelve volunteer subjects, using the product of Exam
`ple 4.
`FIG. 10 is a graph as in FIG. 9 using the product of
`Example 5.
`FIG. 11 is a graph showing dissolution rates in curves
`plotting the percentage dissolution against time after
`administration of each pH of 1.5, 3.0 and 7.5, for the
`product of Example 6.
`». FIG. 12 is a graph as in FIG. 11 for the product of
`Example 7.
`FIG. 13 is a graph having curves showing plasma
`levels of drug as a function of time as a mean of the total
`number of subjects tested for the product of Example 6,
`the product of Example 7 and the conventional tablet
`Persantine.
`FIG. 14 is a graph as in FIG. 13 with curves for the
`product of Example 8 and the commercial tablet Aldo
`met.
`FIG. 15 is a graph as in FIG. 13 with curves for the
`product ‘of Example 9 and the commercial tablet Ind
`eral.
`FIG. 16 is ‘.1 graph as in FIG. 13 with curves for the
`product of U‘ample l0 and loose ?lled capsules of dil
`tiazem.
`
`4
`FIG. 17 is a graph showing dissolution rates in curves
`plotting the percentage dissolution against time after
`administration at each pH of 1.5, 3.0 and 6.0 for the
`product of Example 11 (curves d-f) and a commercial
`product (curves a-c).
`DETAILED DESCRIPTION OF PREFERRED
`EMBODIMENTS
`According to the present invention there is provided
`a process for the preparation of pharmaceutical forms
`with delayed action, characterized in that the applica
`tion solutions of the excipients, of the coatings and of
`the active constituients are adjusted to a desired pH.
`This adjustment of the pH of the application solutions
`has the effect of more uniformly modifying the pH of
`the environment inside the pellet, the tablet or the like
`by countering the hostile environment which exists
`outside of the pellet, of the tablet or the like. In an
`advantageous embodiment of the process accordingto
`the invention, the application solutions are adjusted to
`an alkaline pH by means of organic and/or inorganic
`bases and/or basic salts. According to another advanta
`geous embodiment of the process according to the in
`vention, the application solutions are adjusted to an acid
`pH by means of organic acids and/or acid salts.
`The description which follows refers to examples of
`manufacture of the novel galenic form, to comparison
`tests of solubilities as well as to clinical tests of determi
`nation of the levels of medicaments in the blood.
`It must of course be understood however that these
`examples and clinical tests are given solely by way ‘of
`illustration of the process and product according to the
`invention, of which they do not constitute a limitation
`thereof in any way.
`One of the factors affecting the blood levels of a drug
`is its solubility in the pH environment in which it finds
`itself in the gastro-intestinal tract after oral administra
`tion. If the drug is poorly soluble, it will be poorly
`absorbed from the gastro-intestinal tract into the blood.
`Many drugs-are either weakly acidic or alkaline. The
`solubility of a weak acid or base usually varies consider
`ably as a function of pH, and the pH of the gastro-intes
`tinal tract varies from very acidic pH values in the
`stomach to slightly alkaline values in the small intestine.
`The solubility of weak acids is greatest in alkaline solu
`tion, whereas the solubility of weak bases is greatest in
`acidic solutions.
`-
`According to the present invention, a dosage form is
`produced in such a manner that a pH-adjusted micro
`environment is created in which the solubility of the
`drug is maintained substantially constant. This results in
`an improved blood level pro?le.
`>
`A second situation in which the creation of a pH
`adjusted micro-environment results in an improved
`blood level profile is where a drug is unstable in the acid
`pH found in the stomach. A dosage form in accordance
`with the present invention, in which a pH-adjusted
`micro-environment is created protects the acid-unstable
`drugs from acid hydrolysis in the stomach.
`The present invention creates such a pH-adjusted
`micro-environment, preferably, by causing the pH of all
`coating solutions to be adjusted, as well as the pH of
`every application solution, and every layer of active
`component. In conventional dosage forms, it is common
`to use a pellet or tablet of sugar as the core, or a tablet
`of active principle as a core, to which are applied appli
`cation solutions of excipients and coatings such as poly
`vinyl pyrrolidone, gum lacquer, waxes, syrups, etc., as a
`
`55
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`60
`
`65
`
`

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`5
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`15
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`20
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`5,051,262
`6
`pH-adjusting agent in accordance with the present in
`vention.
`'
`As is common in the art, the formulations of the pres
`ent invention will generally include a dissolution con
`troller which determines the rate at which the drug is
`released. Some well known dissolution controllers in~
`clude polyvinyl pyrrolidone, polyvinyl acetate phthal
`ate, cholesteryl acetate, glucose, shellac, cellulose, ethyl
`cellulose, the methacrylates, the acetophalates, etc.
`The amount of pH-adjusting agent to be added will -
`depend upon the particular medicament, as well as the
`size of the dosage formulation. Ideally, as much pH
`adjusting agent as possible should be added, as the more
`pH-adjusting agent present, the better ability there is to
`maintain constant solubility properties. In practice,
`however, it is not possible to add as much pH-adjusting
`agent as would be desirable, and so as much is added as
`possible, given the size and weight constraints of the
`unit dosage. It is preferred that the pH adjusting agent
`be added to every application solution, coating and
`layer or core of active principle used in formulating the
`tablet or capsule, starting with the innermost layer or
`core of active principle. Every such layer or application
`solution must have the same type of pH adjustor (acid
`or alkaline), and, preferably, the same pH-adjusting
`agent.
`The process of the present invention is applicable to
`any known process of making delayed action or con
`trolled release medicaments. For example, one well
`known method of making such formulations is to start
`with a sugar granule which is coated with active princi
`ple by means of an application solution, and which is
`then coated with a desired number of layers of delayed
`release coating. In other processes, multiple layers of
`pharmaceuticals are applied, possibly with layers of
`delayed release material therebetween. The dosage unit
`may be built up into a single tablet, or may be made into
`a plurality of granules which are administered together
`in the form of a‘ capsule. Any of these known methods‘
`may be used in accordance with the present invention,
`including any known dissolution controller, coating
`agent, delayed release material, etc., with the proviso
`that in accordance with the most preferred embodiment
`present invention, every layer of the active principle,
`every application solution applied, every solution of
`coating, etc., starting with the innermost layer of active
`principle, must have a pH~adjusting agent added
`thereto, so that the micro-environment of the active
`principle will immediately attain the desired pH and this
`desired pH will be maintained throughout the course of
`travel of the drug through the gastro-intestinal tract.
`The following examples and the graphs which relate
`thereto and are shown in the accompanying drawings
`illustrate methods and products in accordance with the
`present invention. It must be understood that the pres
`ent invention is not intended to be limited to the materi
`als used in the following examples.
`
`45
`
`5
`means for moistening the pellets or tablets to cause the ’
`adherence thereto of subsequent layers of active com
`ponent. In accordance with the present invention, the
`core sugar pellet need not have pH-adjusting agent
`added thereto, as long as the innermost layer or tablet of
`active principle has pI-I-adjusting agent added thereto,
`and, preferably, all other application s