CA1289076C - Pharmaceutical preparation with controlled and delayed release of active substance and process for the preparation thereof - Google Patents
Pharmaceutical preparation with controlled and delayed release of active substance and process for the preparation thereofInfo
- Publication number
- CA1289076C CA1289076C CA000514139A CA514139A CA1289076C CA 1289076 C CA1289076 C CA 1289076C CA 000514139 A CA000514139 A CA 000514139A CA 514139 A CA514139 A CA 514139A CA 1289076 C CA1289076 C CA 1289076C
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- Canada
- Prior art keywords
- active substance
- carrier material
- pharmaceutical composition
- range
- emulsion
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Macromonomer-Based Addition Polymer (AREA)
- Polyesters Or Polycarbonates (AREA)
- Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Saccharide Compounds (AREA)
Abstract
Abstract Controlled and delayed release pharmaceutical composition The present invention provides a controlled and delayed release pharmaceutical composition comprising a carrier material and a pharmaceutically active substance, said carrier material comprising an emulsion polymer polymerized to a particle size in the range of from 50 to 500 nm and a glass temperature in the range of from -20°C to +80°C. The invention also provides processes for preparing said pharmaceutical compositions.
Description
7~
~ontrol].ed and delayed release ~harmaceutical composition The present invention relates to a controlled and delayed release pharmaceutical composition, and more particularly to a composition comprising a pharmaceutically active substance and at least one carrier material allowing the controlled and delayed release of the active substance. The invention ~urther relates to a process for preparing said pharmaceutical composition.
It is known to produce pharmaceutical compositions in the form of capsules, tabl.ets and films which ensure a constant release of active substance and thus maintain a constant concentration of the active substance in the body. In capsules and tablets the release of the active substance is usually controlled by means of suitable coatings, e.g. as in : the case of film coated tablets. Sustained-release forms may also be prepared from granulated mixtures o~ different carriers which release the pharmaceuti-cally active substance at ~ifferent rates~ A di.visible ~ablet with del.ayed release of the active substance is disclosed for example in DE-A-33 14 003; this tablet is prepared from an emulsion-polymerised p~lyacryIate, and the rate of release of active substance is controlled by means of the granule size and granule size distribution.
In systems for transdermal application, the reIeas-e of the active substance may be adjusted by means of a special membrane (see for example US-A-3 731 683) or with the aid o~ adjuvants, for example ami.nes, fats or higher alcohols.
, ~ ':
~2~39~'7~
However, the delayed release pharmaceutical composi-tions clescribed in the prior art have not always proved entirely satisfactory in practice. A reason for this is that tablets coate~ with a film alter the;r active sub.stance release characteristics after being divided up. A further reason is that the possibility of controlling the release of active substance by means of the granule size, (see D~-A-33-14 003), is limited by the fact that the granule size cannot be freely selected. As a result of technical problems such as inhomogeneity and the required minimum number of granules charged with active substance, the granule size in practice has an upper and a lower limit, with the result ~hat the optimum release rate for the active substance canno~ be achieved in every case.
Surprisingly, we have now found that, for a pharmaceu-tical composition consisting of an emulsion-polymerised carrier material, the rate of release can be adjusted by simply varying the particle size of the emulsion-polymerised polymer be~ds and by varying the glass temperature of the polymer.
The "particle size" refers to th-e diameter o tbe particles of the polymeric carrier material after ?5 they have been produced. Suitable particle sizes according to the invention are in the range of from 50 to 500 nm. ~he particle size (diameter~
can be adjusted as a function o the polymerisation conditions~ ~ reduction in particle size will lead to an increase in the rate of release.
Thus accor~ing to one aspect the present invention provides a controlled and delayed release pharmaceutical composition comprising a carrier material and a pharmaceutically active substance, said carrier ' ' :
', : . , ~ 28!~13~7~
material comprising an emulsion polymer ~olymerized to a particle size in the range of from 50 to 500 nm and a glass temperature in the ran~e of ~rom -20~
to +80C.
One preferred active substance is clonidine or a physiologically acceptable addition salt thereof.
However other pharmaceutically active substances for which delayed and controlled release is desirable may of course be used.
Where the composition of the invention comprises the active substance and carrier in powdered (e.g.
granulated~ form, for example where the composition is in tablet or capsule form, then by a combination of varying the granule size, the particle size and the glass temperature, it is possible to adjust the release characteristics for ~he active substance within a wide range.
In the case of pharmaceutical compositions in the form of transdermal films on the other hand, the rate of release may be adjusted by varying the particle size and the glass temperature and the thickness of the active substance containing layer.
The layer thickness may conveniently be varied in the range of ~rom 40 to 200 microns, preferably from 60 to 140 microns.
The glass temperature may be adiusted by altering the mon~mer composition from which the polymeric carrier material is formed. According to the invention the glass tempera~ure is suitably in the range of -20C to +80C, preferably from -20 to ~40C, more particularly from -10 to +30C. Any increase in the glass temperature leads to a reduction in the rate o~ release.
,. , ~.. ..
, .
~8~7~;
For compositions comprisiny the carrier material and the active subtance in powdered (i.e. qranulated) form, the granule size is conveniently in the ran~e from 10 to 500 microns. In order to adjust the granule size, the emulsion-polymerised polymer having a selected particle size may be dissolved together with the active substance in a suitable solventr then poured out to form a film and the solvent is evaporated o~f. The film may then be ground to the desired granule size, possibly below its glass temperature, and screened if necessary.
Hencer according to a further aspect, the present invention provides a process for preparing a pharrna-ceutical composition wherein an emulsion polymerized carrier material polymerized to a particle size in the range of from 50 to 500 nm and a ylass tempera-ture in the range of from -20C to ~80C as herein-before described is dissolved or dispersed in an organic solvent together-~ith a ~harmaceutically ac-tive substance, the solven~ is evaporated off, the solid residue is ground ~o form a granulate having a granule size ; in the range of from 10 to 500 microns and the granulate is processed into adminlstrable dosage units.
In the process of the invention, the granulate is ; preferably obtainecl by granulation below the ~lass temperture and suitably, optionally together with a pharmaceutical excipient or diluent, is compressed into tablets or filled into capsules.
According to another aspect the invention provides a ~ne~hod of preparing a pharmaceutical composition as hereinbefore described wherein an emuls;on poly-merized carrier material polymerized to a Particle slze in the range of from 50 to 500 nm and a glass temperature in the range of from -20C to ~80C
'~ ' , 3L2~7~
as hereinbefore descrihed is dissolved i.n an organic solvent together with a pha~maceutically active substance, the resulting solution is poured to form a film from whi.ch the solvent i.s evaporated off, and the film formed is provided with a vapour-impermeable backing layer and optionally also with an adhesive layer.
The carrier material may consist of polymers or copolymers which can be produced by emulsion polymeri-sation, such as polyvinylchloride, polylactides,polystyrene, polyvinylacetate, polyhutadiene, polyacryl-onitrile, polyvinylesters, polyvinylethers and the copolymers thereof~ Emulsion-polymerised copolymers of methyl and/or ethyl esters of acrylic and methacrylic acid are preferred. The molecular weight of the emulsion polymers is convenently in the range of from 104 to 107. In its production, the carrier material may be recovered in solid form, for example by freeze-drying; the polymer particles then retain their shape and size.
The pharmaceutical composition according ~o the invention ma.y be produced by dissolving or suspending an emulsion polymer of the ~esired particle size and glass temperature together with the active s-ubstance 2,5 in as volatile a solvent as possible.
Suitable solvents ~or the solution or suspens.ion containing the active substance and emulsion polymer include those having a low evaporation point, e.g.
low-boiling alcohols such as met.hanol, ethanol, aceton.e, methylethylketone, halogenated hydrocarbons such as methylene chloride, methyl and ethyl acetate, methyl and ethyl acetoacetate, ethers such as tetrahydrofuran and dioxan, dimethylsulphoxide, and low boiling freons, and mixtures of two or more of these solvents.
~L28~
The rate of release of the active substance may additionalJy be varied bv means of adjuvants, ;.e.
suhstances which will influence diff~sion. These so-called ad~uvants include, for example, polyvinyl-pyrrolidone, cellulose esters, amines, fats andhigher alcohols. If desired, these substances may be added to the solution of active substance.
This solution may be urther processed as follows:
In order to prepare a pharmaceutica:L composition containing the active substance in the form of a film for transdermal therapeutic application, the solution obtained is poured out to form a film of a defined layer thickness the dimensions of~which are such that after evaporation of the solvent the lS film conveniently has a layer thickness in the range of from 40 to 200 microns, preferably between 60 and 140 microns~ The film may then be provided with a vapour-impermeable backing layer and optionally an adhesive layer and may then be packaged.
In order to produce a p~armaceutical composition containing ~he active substance in powder form, the solvent of the solution described above, is eliminated, optionally te.g. in the case of pharma-~ ceutical compositions susceptible to moisture or oxidation~ under an inert ~as, and the residue obtainedis ground up to the desired granule size of from 10 to 500 microns, preferably at a temperature below its glass temperature. I~ necessary, grinding may also be carried out in the presence of a filler, e.g. an inert excipient, carrier or diluent such as lactose, magnesium stearate, ~inely divided silica or similar flnely divided lubricants. The mass ratio of active substance-containing emulsion polymer to finely divided ~iller may vary within wide limits and conveniently ranges Çrom about 10:1 to 1:4.
Further processing to form tablets or capsules may be carried out by known metho~s, optionally using conventional excipients such as ~inders, inert fillers, lubricants and disintegrants.
A preferred embodiment of the com~osition of the invention is in the form of a divisible tablet, since the composition according to the invention retains its advantageous properties even when frag-mented. When producing films for transdermal appli-cation, the rate of release for a given film thickness and quantity of pharmaceutical substance incorporated may be ad~usted by varying the particle size and the glass temperature of the carrier material.
It is known that the rate of release increases substan-tially when the load on the carrier material is increased, with the result that sustained release of the active substance can no longer be guaranteed.
This could be compensated by increasing the ~ranule size, bu~ there would then be a risk that the minimum number of loaded granules in a tablet would ~all below the critical number o~ 400 ~below which homo-geneous distribution of the pharmaceutical active substance from tablet to tablet is no longer guaranteed).
; According to the invention, the problem can be solved by selecting a higher glass temperature for the emulsion-polymerised carrier material and a larger particle size, whilst the granule size may be kept substantially constan~. This makes it possible to load the carrier material with a substantially greater quan~ity o~ pharmaceutical substance in the case of tablets, capsules or films.
With the use of the invention, it is also possible to achieve more Favourable ratios of pharmaceutically : .-- .' ' :
. .
-. ~. , .
~2~ 6 active substance to carrier and hence to extend the sustained-release ~rinciple to pharmaceutically active .substances admi.nistered in hiqher doses since the rate of ~elease can be adj~sted withi.n a wide range even with higher loads of active substance by means of the parameters of particle size, granuIe size and glass temperature described above.
Generally, the compositions according to the invention preferably contai.n from 0.1 to 30~ by weight, more preferably from 1 to 10% by weight of active substance.
The following ~xamples are intended to illustrate the invention in a non-limiting manner (unless other~
wise stated, all ratios and percentages are~ by weight~.
The release characteristics of compositions according to the invention are further illustrated in the accompanying drawings, in which:-Figure I is a graph showing as a function of timethe percentage release of clonidine from compositons according ~o the invention in the form of films for trans~ermat ap~lictionr and Figure II is a graph showing as a function of time the perce~tage release of Azepe~ol from compositons accor-ding to the in~ention in the form of tablets.
~Z8~
g Examples ~) Films:
-Example lThe emulsion-polymerised polyacrylates listed in Table I are processed to form transdermal films and tested ~or their rates of release.
Table I: Emulsion-polymerised polyacrylate Carrier Glass temperature Diameter of polyacrylate latex particles A - 8C 50 - 100 nm B + 29C 50 - 100 nm C - 8C 100 - lS0 nm The polyacrylate latex particles are obtained by drying off the water from the relevant dispersion (carrier A is Eudragit E 30 D from Rohm GmbHI Darmstadt; carriers B B and C are of the same polymer material but differ in particle diameter and in glass temperature~. 21.3 g of the dried polyacrylate are dissolved together with 1.6 g of clonidine in 142 g of acetone and poured onto a flat surface to form a film. The layer thickness after evaporation of the solvent.is 80 microns. The rate of , release was determined in the presence of an aqueous medium, p~ 7, at 37C, and the release analysis was ' performed using HPLC.
The diffusion coefficients obtai.ned for the three different types of polyacrylate latex are listed in Table II:
r ~
, ;
;' , ~s~
Table II:
(~arrier Diffusion coefficient D [cm2/dayl A 5.5xlO 6 B 4.4xlO 6 C 1.4xlO 6 Fig. I of the accompanying drawings shows the rates of release or the three physically diferent poly-acrylate carrier materials A, B and C. As is clear from the curves, the release characteristics may be influenced both by the part.icle size and by the glass temperature of the polyacrylate latices.
:.
: ~ :
:
,--:
:
.
.
~L25~
~xample_ :
The emulsion-polymerised copolymers o~ vinyl chloride and acrylic acid ester listed in Table III are processed to ~orm transdermal films and tested for their rate of release.
Table III
Carrier H
_ 10 Solid content of polymers i.n 44.6 % 44.7 %
the dispersion Film forming temperature ~ ~lass temperature) 67~C 0C
Diameter of the polymer 15 particles (particle size~ 261 nm 262 nm :
! The two carrier materials G and H (VA 381 A and VA 381 B) obtained by emulsion polymerisation differ in their glass tempera~ure and hence in the softness of the polymer; the particle si~e however is similar for both pro~ucts. The polymer is obtained by drying the aqueous dispersion, then it is dissolved toge~her with the pharmaceuticaIly active substance clonidine in methylene chloride and poured out in known manner to form films with a layer th.ickness of about 100 microns. The release of pharmaceutically active substance rom a controlled percutaneous application (CPA) f-ilm measuring 3 cm2 is determined in a USP
tester and the content is analysed by HPLC.
The quantities of clonidine released (in percent) for various times is shown in Table IV. The rates of release decrease w.i.th increasing glass temperature, i.e. the harder the vinyl chrolide/acrylate latex the slower the release.
:~, 7~
Table IV
~antity of clonidine release in Time in ~ays ~arrier ~. Carrier 0.33 26.3 50.9 1 47.2 67.7 4 ,66.8 73.0 70.2 74.4 ....
Film th.ickness: 100 microns, loading quantity 0.7 mg clonidine/cm2 ; B) TabletS:
Three different types of polyacrylate are each processed together with an.active substance to form tablets and the release characteristics thereof are shown in Fig. II.
The polymer carriers D and E are emulsion-polymerised polyacrylates (as with carriers B and C above, they are of the same polymer material as Eudrayit E 30 of Rohm GmbH), and polymer carrier F (Eudragit RS 100) is a bulk-polymerised polyacrylate also available from Rohm GmbH. The two carrier : types E and F have approximately the same glass temperature (rrg = 30C~, but are in physically different forms: E is a latex in bead form and F is in the form of polymer coils.
~ The glass temperature of polyacrylate carrier D, also a latex in bead form, is Tg = -8C. The glass temperature may be adjuste~ by varying the proportions of monomers making up khe polymer, whilst the shape may be altered by varying the conditions of polymerisation.
~xample 3 23.75 g of polymer carrier E are stirre~ with 400 ml of acetone in a suitable container until a clear sol~tion is forme~, then the solution of active substance consisting of 1.25 g of B-HT 933 base (Azepexol, Boehringer Ingelheim) in 100 ml of methanol is adde~. The solvent is evaporated of~ from the resulting solution under a protective gas atmosphere (N2) and the remaining film charged with active substance is cooled to about -40C using dr~ ice and ground in batches together w;th lactose in a ratio of 9:1 in a mill with rotating bla~es, with cooling. A free-flowing pow~er is obtained in which the polyacrylate loaded with active substance is present in a logarithmically normal distribution of between 65 and 500 microns.
The mixture obtained as described above is compressed in a further operation, by conventional methods, with conventional ~ablet-making excipients such as lactose, corn starch, colloidal silica and/or magnesium stearate, to form tablets which contain a 5% charge of active substance based on the polymer carrier. (B-H~ 933 is 2-amino-6-ethyl-4,5,7,8-tetrahydro~6H-oxazolo[5,4,-d]azepine).
Example 4 Analogously to Example 3, 95 g of polyacrylate carrier E, dissolved in 500 ml of acetone and 5.0 g of B-HT 933 base in 40 ml of methanol are processed to form a film, which is then ground up and compressed into tablets.
Comparativ ~
Analogously to Example 3, 95 g of polymer carrier F
dissolved in 250 ml of dichloromethane and 5.0 g `
~8~
of ~-~T 933 hase j.n 40 ml of methanol are processed to form a film which ;s then ground up and compressed into tablets.
The _ vitro release of the active substance from the tablets was tested at 37C i.n a USP XVII tester, using water at pH 7 as the receptor medium. Analysis was performed by ~PLC.
As is clear from Fig. II, the active substance has been almost totally released from the bulk polymerised polyacrylate after only 2 hours, whereas in the case of an emulsion-polymerised polyacrylate any desired release profile, e.g. tlh 19~, t6h 60~ release of pharmaceu~ically active substance, may be achieved by selection of the glass temperature.
~ontrol].ed and delayed release ~harmaceutical composition The present invention relates to a controlled and delayed release pharmaceutical composition, and more particularly to a composition comprising a pharmaceutically active substance and at least one carrier material allowing the controlled and delayed release of the active substance. The invention ~urther relates to a process for preparing said pharmaceutical composition.
It is known to produce pharmaceutical compositions in the form of capsules, tabl.ets and films which ensure a constant release of active substance and thus maintain a constant concentration of the active substance in the body. In capsules and tablets the release of the active substance is usually controlled by means of suitable coatings, e.g. as in : the case of film coated tablets. Sustained-release forms may also be prepared from granulated mixtures o~ different carriers which release the pharmaceuti-cally active substance at ~ifferent rates~ A di.visible ~ablet with del.ayed release of the active substance is disclosed for example in DE-A-33 14 003; this tablet is prepared from an emulsion-polymerised p~lyacryIate, and the rate of release of active substance is controlled by means of the granule size and granule size distribution.
In systems for transdermal application, the reIeas-e of the active substance may be adjusted by means of a special membrane (see for example US-A-3 731 683) or with the aid o~ adjuvants, for example ami.nes, fats or higher alcohols.
, ~ ':
~2~39~'7~
However, the delayed release pharmaceutical composi-tions clescribed in the prior art have not always proved entirely satisfactory in practice. A reason for this is that tablets coate~ with a film alter the;r active sub.stance release characteristics after being divided up. A further reason is that the possibility of controlling the release of active substance by means of the granule size, (see D~-A-33-14 003), is limited by the fact that the granule size cannot be freely selected. As a result of technical problems such as inhomogeneity and the required minimum number of granules charged with active substance, the granule size in practice has an upper and a lower limit, with the result ~hat the optimum release rate for the active substance canno~ be achieved in every case.
Surprisingly, we have now found that, for a pharmaceu-tical composition consisting of an emulsion-polymerised carrier material, the rate of release can be adjusted by simply varying the particle size of the emulsion-polymerised polymer be~ds and by varying the glass temperature of the polymer.
The "particle size" refers to th-e diameter o tbe particles of the polymeric carrier material after ?5 they have been produced. Suitable particle sizes according to the invention are in the range of from 50 to 500 nm. ~he particle size (diameter~
can be adjusted as a function o the polymerisation conditions~ ~ reduction in particle size will lead to an increase in the rate of release.
Thus accor~ing to one aspect the present invention provides a controlled and delayed release pharmaceutical composition comprising a carrier material and a pharmaceutically active substance, said carrier ' ' :
', : . , ~ 28!~13~7~
material comprising an emulsion polymer ~olymerized to a particle size in the range of from 50 to 500 nm and a glass temperature in the ran~e of ~rom -20~
to +80C.
One preferred active substance is clonidine or a physiologically acceptable addition salt thereof.
However other pharmaceutically active substances for which delayed and controlled release is desirable may of course be used.
Where the composition of the invention comprises the active substance and carrier in powdered (e.g.
granulated~ form, for example where the composition is in tablet or capsule form, then by a combination of varying the granule size, the particle size and the glass temperature, it is possible to adjust the release characteristics for ~he active substance within a wide range.
In the case of pharmaceutical compositions in the form of transdermal films on the other hand, the rate of release may be adjusted by varying the particle size and the glass temperature and the thickness of the active substance containing layer.
The layer thickness may conveniently be varied in the range of ~rom 40 to 200 microns, preferably from 60 to 140 microns.
The glass temperature may be adiusted by altering the mon~mer composition from which the polymeric carrier material is formed. According to the invention the glass tempera~ure is suitably in the range of -20C to +80C, preferably from -20 to ~40C, more particularly from -10 to +30C. Any increase in the glass temperature leads to a reduction in the rate o~ release.
,. , ~.. ..
, .
~8~7~;
For compositions comprisiny the carrier material and the active subtance in powdered (i.e. qranulated) form, the granule size is conveniently in the ran~e from 10 to 500 microns. In order to adjust the granule size, the emulsion-polymerised polymer having a selected particle size may be dissolved together with the active substance in a suitable solventr then poured out to form a film and the solvent is evaporated o~f. The film may then be ground to the desired granule size, possibly below its glass temperature, and screened if necessary.
Hencer according to a further aspect, the present invention provides a process for preparing a pharrna-ceutical composition wherein an emulsion polymerized carrier material polymerized to a particle size in the range of from 50 to 500 nm and a ylass tempera-ture in the range of from -20C to ~80C as herein-before described is dissolved or dispersed in an organic solvent together-~ith a ~harmaceutically ac-tive substance, the solven~ is evaporated off, the solid residue is ground ~o form a granulate having a granule size ; in the range of from 10 to 500 microns and the granulate is processed into adminlstrable dosage units.
In the process of the invention, the granulate is ; preferably obtainecl by granulation below the ~lass temperture and suitably, optionally together with a pharmaceutical excipient or diluent, is compressed into tablets or filled into capsules.
According to another aspect the invention provides a ~ne~hod of preparing a pharmaceutical composition as hereinbefore described wherein an emuls;on poly-merized carrier material polymerized to a Particle slze in the range of from 50 to 500 nm and a glass temperature in the range of from -20C to ~80C
'~ ' , 3L2~7~
as hereinbefore descrihed is dissolved i.n an organic solvent together with a pha~maceutically active substance, the resulting solution is poured to form a film from whi.ch the solvent i.s evaporated off, and the film formed is provided with a vapour-impermeable backing layer and optionally also with an adhesive layer.
The carrier material may consist of polymers or copolymers which can be produced by emulsion polymeri-sation, such as polyvinylchloride, polylactides,polystyrene, polyvinylacetate, polyhutadiene, polyacryl-onitrile, polyvinylesters, polyvinylethers and the copolymers thereof~ Emulsion-polymerised copolymers of methyl and/or ethyl esters of acrylic and methacrylic acid are preferred. The molecular weight of the emulsion polymers is convenently in the range of from 104 to 107. In its production, the carrier material may be recovered in solid form, for example by freeze-drying; the polymer particles then retain their shape and size.
The pharmaceutical composition according ~o the invention ma.y be produced by dissolving or suspending an emulsion polymer of the ~esired particle size and glass temperature together with the active s-ubstance 2,5 in as volatile a solvent as possible.
Suitable solvents ~or the solution or suspens.ion containing the active substance and emulsion polymer include those having a low evaporation point, e.g.
low-boiling alcohols such as met.hanol, ethanol, aceton.e, methylethylketone, halogenated hydrocarbons such as methylene chloride, methyl and ethyl acetate, methyl and ethyl acetoacetate, ethers such as tetrahydrofuran and dioxan, dimethylsulphoxide, and low boiling freons, and mixtures of two or more of these solvents.
~L28~
The rate of release of the active substance may additionalJy be varied bv means of adjuvants, ;.e.
suhstances which will influence diff~sion. These so-called ad~uvants include, for example, polyvinyl-pyrrolidone, cellulose esters, amines, fats andhigher alcohols. If desired, these substances may be added to the solution of active substance.
This solution may be urther processed as follows:
In order to prepare a pharmaceutica:L composition containing the active substance in the form of a film for transdermal therapeutic application, the solution obtained is poured out to form a film of a defined layer thickness the dimensions of~which are such that after evaporation of the solvent the lS film conveniently has a layer thickness in the range of from 40 to 200 microns, preferably between 60 and 140 microns~ The film may then be provided with a vapour-impermeable backing layer and optionally an adhesive layer and may then be packaged.
In order to produce a p~armaceutical composition containing ~he active substance in powder form, the solvent of the solution described above, is eliminated, optionally te.g. in the case of pharma-~ ceutical compositions susceptible to moisture or oxidation~ under an inert ~as, and the residue obtainedis ground up to the desired granule size of from 10 to 500 microns, preferably at a temperature below its glass temperature. I~ necessary, grinding may also be carried out in the presence of a filler, e.g. an inert excipient, carrier or diluent such as lactose, magnesium stearate, ~inely divided silica or similar flnely divided lubricants. The mass ratio of active substance-containing emulsion polymer to finely divided ~iller may vary within wide limits and conveniently ranges Çrom about 10:1 to 1:4.
Further processing to form tablets or capsules may be carried out by known metho~s, optionally using conventional excipients such as ~inders, inert fillers, lubricants and disintegrants.
A preferred embodiment of the com~osition of the invention is in the form of a divisible tablet, since the composition according to the invention retains its advantageous properties even when frag-mented. When producing films for transdermal appli-cation, the rate of release for a given film thickness and quantity of pharmaceutical substance incorporated may be ad~usted by varying the particle size and the glass temperature of the carrier material.
It is known that the rate of release increases substan-tially when the load on the carrier material is increased, with the result that sustained release of the active substance can no longer be guaranteed.
This could be compensated by increasing the ~ranule size, bu~ there would then be a risk that the minimum number of loaded granules in a tablet would ~all below the critical number o~ 400 ~below which homo-geneous distribution of the pharmaceutical active substance from tablet to tablet is no longer guaranteed).
; According to the invention, the problem can be solved by selecting a higher glass temperature for the emulsion-polymerised carrier material and a larger particle size, whilst the granule size may be kept substantially constan~. This makes it possible to load the carrier material with a substantially greater quan~ity o~ pharmaceutical substance in the case of tablets, capsules or films.
With the use of the invention, it is also possible to achieve more Favourable ratios of pharmaceutically : .-- .' ' :
. .
-. ~. , .
~2~ 6 active substance to carrier and hence to extend the sustained-release ~rinciple to pharmaceutically active .substances admi.nistered in hiqher doses since the rate of ~elease can be adj~sted withi.n a wide range even with higher loads of active substance by means of the parameters of particle size, granuIe size and glass temperature described above.
Generally, the compositions according to the invention preferably contai.n from 0.1 to 30~ by weight, more preferably from 1 to 10% by weight of active substance.
The following ~xamples are intended to illustrate the invention in a non-limiting manner (unless other~
wise stated, all ratios and percentages are~ by weight~.
The release characteristics of compositions according to the invention are further illustrated in the accompanying drawings, in which:-Figure I is a graph showing as a function of timethe percentage release of clonidine from compositons according ~o the invention in the form of films for trans~ermat ap~lictionr and Figure II is a graph showing as a function of time the perce~tage release of Azepe~ol from compositons accor-ding to the in~ention in the form of tablets.
~Z8~
g Examples ~) Films:
-Example lThe emulsion-polymerised polyacrylates listed in Table I are processed to form transdermal films and tested ~or their rates of release.
Table I: Emulsion-polymerised polyacrylate Carrier Glass temperature Diameter of polyacrylate latex particles A - 8C 50 - 100 nm B + 29C 50 - 100 nm C - 8C 100 - lS0 nm The polyacrylate latex particles are obtained by drying off the water from the relevant dispersion (carrier A is Eudragit E 30 D from Rohm GmbHI Darmstadt; carriers B B and C are of the same polymer material but differ in particle diameter and in glass temperature~. 21.3 g of the dried polyacrylate are dissolved together with 1.6 g of clonidine in 142 g of acetone and poured onto a flat surface to form a film. The layer thickness after evaporation of the solvent.is 80 microns. The rate of , release was determined in the presence of an aqueous medium, p~ 7, at 37C, and the release analysis was ' performed using HPLC.
The diffusion coefficients obtai.ned for the three different types of polyacrylate latex are listed in Table II:
r ~
, ;
;' , ~s~
Table II:
(~arrier Diffusion coefficient D [cm2/dayl A 5.5xlO 6 B 4.4xlO 6 C 1.4xlO 6 Fig. I of the accompanying drawings shows the rates of release or the three physically diferent poly-acrylate carrier materials A, B and C. As is clear from the curves, the release characteristics may be influenced both by the part.icle size and by the glass temperature of the polyacrylate latices.
:.
: ~ :
:
,--:
:
.
.
~L25~
~xample_ :
The emulsion-polymerised copolymers o~ vinyl chloride and acrylic acid ester listed in Table III are processed to ~orm transdermal films and tested for their rate of release.
Table III
Carrier H
_ 10 Solid content of polymers i.n 44.6 % 44.7 %
the dispersion Film forming temperature ~ ~lass temperature) 67~C 0C
Diameter of the polymer 15 particles (particle size~ 261 nm 262 nm :
! The two carrier materials G and H (VA 381 A and VA 381 B) obtained by emulsion polymerisation differ in their glass tempera~ure and hence in the softness of the polymer; the particle si~e however is similar for both pro~ucts. The polymer is obtained by drying the aqueous dispersion, then it is dissolved toge~her with the pharmaceuticaIly active substance clonidine in methylene chloride and poured out in known manner to form films with a layer th.ickness of about 100 microns. The release of pharmaceutically active substance rom a controlled percutaneous application (CPA) f-ilm measuring 3 cm2 is determined in a USP
tester and the content is analysed by HPLC.
The quantities of clonidine released (in percent) for various times is shown in Table IV. The rates of release decrease w.i.th increasing glass temperature, i.e. the harder the vinyl chrolide/acrylate latex the slower the release.
:~, 7~
Table IV
~antity of clonidine release in Time in ~ays ~arrier ~. Carrier 0.33 26.3 50.9 1 47.2 67.7 4 ,66.8 73.0 70.2 74.4 ....
Film th.ickness: 100 microns, loading quantity 0.7 mg clonidine/cm2 ; B) TabletS:
Three different types of polyacrylate are each processed together with an.active substance to form tablets and the release characteristics thereof are shown in Fig. II.
The polymer carriers D and E are emulsion-polymerised polyacrylates (as with carriers B and C above, they are of the same polymer material as Eudrayit E 30 of Rohm GmbH), and polymer carrier F (Eudragit RS 100) is a bulk-polymerised polyacrylate also available from Rohm GmbH. The two carrier : types E and F have approximately the same glass temperature (rrg = 30C~, but are in physically different forms: E is a latex in bead form and F is in the form of polymer coils.
~ The glass temperature of polyacrylate carrier D, also a latex in bead form, is Tg = -8C. The glass temperature may be adjuste~ by varying the proportions of monomers making up khe polymer, whilst the shape may be altered by varying the conditions of polymerisation.
~xample 3 23.75 g of polymer carrier E are stirre~ with 400 ml of acetone in a suitable container until a clear sol~tion is forme~, then the solution of active substance consisting of 1.25 g of B-HT 933 base (Azepexol, Boehringer Ingelheim) in 100 ml of methanol is adde~. The solvent is evaporated of~ from the resulting solution under a protective gas atmosphere (N2) and the remaining film charged with active substance is cooled to about -40C using dr~ ice and ground in batches together w;th lactose in a ratio of 9:1 in a mill with rotating bla~es, with cooling. A free-flowing pow~er is obtained in which the polyacrylate loaded with active substance is present in a logarithmically normal distribution of between 65 and 500 microns.
The mixture obtained as described above is compressed in a further operation, by conventional methods, with conventional ~ablet-making excipients such as lactose, corn starch, colloidal silica and/or magnesium stearate, to form tablets which contain a 5% charge of active substance based on the polymer carrier. (B-H~ 933 is 2-amino-6-ethyl-4,5,7,8-tetrahydro~6H-oxazolo[5,4,-d]azepine).
Example 4 Analogously to Example 3, 95 g of polyacrylate carrier E, dissolved in 500 ml of acetone and 5.0 g of B-HT 933 base in 40 ml of methanol are processed to form a film, which is then ground up and compressed into tablets.
Comparativ ~
Analogously to Example 3, 95 g of polymer carrier F
dissolved in 250 ml of dichloromethane and 5.0 g `
~8~
of ~-~T 933 hase j.n 40 ml of methanol are processed to form a film which ;s then ground up and compressed into tablets.
The _ vitro release of the active substance from the tablets was tested at 37C i.n a USP XVII tester, using water at pH 7 as the receptor medium. Analysis was performed by ~PLC.
As is clear from Fig. II, the active substance has been almost totally released from the bulk polymerised polyacrylate after only 2 hours, whereas in the case of an emulsion-polymerised polyacrylate any desired release profile, e.g. tlh 19~, t6h 60~ release of pharmaceu~ically active substance, may be achieved by selection of the glass temperature.
Claims (20)
1. A controlled and delayed release pharmaceutical composition comprising a carrier material and a pharmaceutically active substance, said carrier material comprising an emulsion polymer polymerized to a particle size in the range of from 50 to 500 nm and a glass temperature in the range of from -20°C
to +80°C.
to +80°C.
2. A pharmaceutical composition as claimed in claim 1, wherein said emulsion polymer has a glass temperature in the range of from -10 to +30°C.
3. A pharmaceutical composition as claimed in claim 1 wherein said carrier material consists of an emulsion-polymerised copolymer.
4. A pharmaceutical composition as claimed in claim 1 or 2 wherein said carrier material comprises an emulsion-polymerised copolymer of methyl and/or ethyl esters of acrylic and methacrylic acid.
5. A pharmaceutical composition as claimed in claim 1, 2 or 3, wherein said active substance is clonidine or a physiologically acceptable addition salt thereof.
6. A pharmaceutical composition as claimed in claim 1, 2 or 3, containing from 0.1 to 30% by weight of said active substance.
7. A pharmaceutical composition as claimed in claim 1, 2 or 3 containing from 1 to 10% by weight of said active substance.
8. A pharmaceutical composition as claimed in claim 1, 2 or 3 wherein said carrier material is present in the form of granules containing said active substance and wherein the granule size is in the range of from 10 to 500 microns.
9. A pharmaceutical composition as claimed in claim 1, 2 or 3 and comprising a film containing said active substance and containing said carrier material and wherein said film has a layer thickness in the range of from 40 to 200 microns.
10. A pharmaceutical composition as claimed in claim 1, 2 or 3 and comprising a film containing said active substance and containing said carrier material and wherein said film has a layer thickness in the range of from 60 to 140 microns.
11. A pharmaceutical composition as claimed in claim 1, 2 or 3 wherein said carrier material comprises an emulsion-polymerized copolymer of methyl and/or ethyl esters of acrylic and methacrylic acid and the active substance is clonidine or a physiologically acceptable addition salt thereof which is present in an amount of from 0.1 to 30% by weight.
12. A process for preparing a pharmaceutical composition wherein an emulsion polymerized carrier material polymerized to a particle size in the range of from 50 to 500 nm and a glass temperature in the range of from -20°C to +80°C as claimed in claim 1 is dissolved or dispersed in an organic solvent together with a pharmaceutically active substance, the solvent is evaporated off, the solid residue is ground to form a granulate having a granule size in the range of from 10 to 500 microns and the granulate is processed into administrable dosage units.
13. A process as claimed in claim 12 wherein said granulate is processed into tablet form or filled into capsules.
14. A process as claimed in claim 12 or 13 wherein as said pharmaceutically active substance is used clonidine or a physiologically acceptable addition salt thereof.
15. A process as claimed in claim 12 or 13 wherein said carrier material comprises an emulsion-polymerised copolymer of methyl and/or ethyl esters of acrylic and methacrylic acid and the active substance is clonidine or a physiologically acceptable addition salt thereof which is present in an amount of from 0.1 to 30% by weight.
16. A method of preparing a pharmaceutical composition as claimed in claim 9 wherein an emulsion polymerized carrier material polymerized to a particle size in the range of from 50 to 500 nm and a glass temperature in the range of from -20°C
to +80°C as claimed in claim 1 is dissolved in an organic solvent together with a pharmaceutically active substance, the resulting solution is poured to form a film from which the solvent is evaporated off, and the film formed is provided with a vapour-impermeable backing layer and optionally also with an adhesive layer.
to +80°C as claimed in claim 1 is dissolved in an organic solvent together with a pharmaceutically active substance, the resulting solution is poured to form a film from which the solvent is evaporated off, and the film formed is provided with a vapour-impermeable backing layer and optionally also with an adhesive layer.
17. A method as claimed in claim 16 wherein as said pharmaceutically active substance is used clonidine or a physiologically acceptable addition salt thereof.
18. A method as claimed in claim 16 wherein said carrier material comprises an emulsion-polymerized copolymer of methyl and/or ethyl esters of acrylic and methacrylic acid and the active substance is clonidine or a physiologically acceptable addition salt thereof which is present in an amount of from 0.1 to 30° by weight.
19. A method for controlling the drug release of a pharmaceutical composition comprising a carrier material and a pharmaceutically active substance, characterized in an emulsion polymerized carrier material comprising an emulsion polymer or copolymer polymerized to a particle size in the range of from 50 to 500 nm and a glass temperature in the range of from -20°C to +80°c, whereby a reduction in particle size will lead to an increase in the rate of release and an increase in the glass temperature leads to a reduction in the rate of release.
20. Use of a composition according to claim 1, 2 or 3 to control or delay release of said pharmaceutically active substance.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19853525767 DE3525767A1 (en) | 1985-07-19 | 1985-07-19 | PHARMACEUTICAL PREPARATION WITH CONTROLLED AND DELAYED ACTIVE SUBSTANCE RELEASE AND METHOD FOR THE PRODUCTION THEREOF |
| DEP3525767.9-41 | 1985-07-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1289076C true CA1289076C (en) | 1991-09-17 |
Family
ID=6276155
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000514139A Expired - Fee Related CA1289076C (en) | 1985-07-19 | 1986-07-18 | Pharmaceutical preparation with controlled and delayed release of active substance and process for the preparation thereof |
Country Status (22)
| Country | Link |
|---|---|
| EP (1) | EP0209121B1 (en) |
| JP (1) | JPH0816068B2 (en) |
| KR (1) | KR930007246B1 (en) |
| AT (1) | ATE72110T1 (en) |
| AU (1) | AU589983B2 (en) |
| CA (1) | CA1289076C (en) |
| CS (1) | CS264133B2 (en) |
| DD (2) | DD265327A5 (en) |
| DE (2) | DE3525767A1 (en) |
| DK (1) | DK343586A (en) |
| ES (1) | ES2001858A6 (en) |
| FI (1) | FI88674C (en) |
| GR (1) | GR861872B (en) |
| HU (1) | HU196314B (en) |
| IE (1) | IE59024B1 (en) |
| IL (1) | IL79439A (en) |
| NO (1) | NO174086C (en) |
| NZ (1) | NZ216897A (en) |
| PH (1) | PH22993A (en) |
| PL (1) | PL260689A1 (en) |
| PT (1) | PT83009B (en) |
| ZA (1) | ZA865363B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9021674D0 (en) * | 1990-10-05 | 1990-11-21 | Ethical Pharma Ltd | Transdermal device |
| DE19603402A1 (en) * | 1995-02-24 | 1996-08-29 | Basf Ag | Soft gelatin capsules |
| DE19940238A1 (en) | 1999-08-25 | 2001-03-01 | Lohmann Therapie Syst Lts | Therapeutic system containing active ingredients for application to the skin with at least two polymer-containing layers |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| USRE28316E (en) * | 1968-09-03 | 1975-01-21 | Entrapment compositions and processes | |
| JPS57116011A (en) * | 1981-01-08 | 1982-07-19 | Nitto Electric Ind Co Ltd | Pharmaceutical preparation |
| DE3204551A1 (en) * | 1982-02-10 | 1983-08-18 | Boehringer Ingelheim KG, 6507 Ingelheim | METHOD FOR PRODUCING A PHARMACEUTICAL PREPARATION IN THE FORM OF A POLYACRYLATE FILM |
| DE3314003A1 (en) * | 1983-04-18 | 1984-10-18 | Boehringer Ingelheim KG, 6507 Ingelheim | DIVISIBLE TABLET WITH DELAYED ACTIVE SUBSTANCE RELEASE AND METHOD FOR THE PRODUCTION THEREOF |
-
1985
- 1985-07-19 DE DE19853525767 patent/DE3525767A1/en not_active Withdrawn
-
1986
- 1986-07-16 EP EP86109726A patent/EP0209121B1/en not_active Expired - Lifetime
- 1986-07-16 DD DD86292545A patent/DD265327A5/en not_active IP Right Cessation
- 1986-07-16 AT AT86109726T patent/ATE72110T1/en not_active IP Right Cessation
- 1986-07-16 DE DE8686109726T patent/DE3683700D1/en not_active Expired - Lifetime
- 1986-07-17 CS CS865452A patent/CS264133B2/en unknown
- 1986-07-17 IL IL79439A patent/IL79439A/en not_active IP Right Cessation
- 1986-07-17 FI FI862967A patent/FI88674C/en not_active IP Right Cessation
- 1986-07-17 PL PL1986260689A patent/PL260689A1/en unknown
- 1986-07-17 GR GR861872A patent/GR861872B/en unknown
- 1986-07-18 HU HU862967A patent/HU196314B/en not_active IP Right Cessation
- 1986-07-18 IE IE191486A patent/IE59024B1/en not_active IP Right Cessation
- 1986-07-18 ZA ZA865363A patent/ZA865363B/en unknown
- 1986-07-18 NO NO862907A patent/NO174086C/en unknown
- 1986-07-18 DK DK343586A patent/DK343586A/en not_active Application Discontinuation
- 1986-07-18 ES ES8600406A patent/ES2001858A6/en not_active Expired
- 1986-07-18 AU AU60304/86A patent/AU589983B2/en not_active Ceased
- 1986-07-18 NZ NZ216897A patent/NZ216897A/en unknown
- 1986-07-18 PT PT83009A patent/PT83009B/en not_active IP Right Cessation
- 1986-07-18 CA CA000514139A patent/CA1289076C/en not_active Expired - Fee Related
- 1986-07-18 JP JP61169644A patent/JPH0816068B2/en not_active Expired - Lifetime
- 1986-07-19 KR KR1019860005857A patent/KR930007246B1/en not_active IP Right Cessation
- 1986-07-21 PH PH34040A patent/PH22993A/en unknown
-
1988
- 1988-04-15 DD DD88314795A patent/DD272604A5/en not_active IP Right Cessation
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