CA1293449C - Controlled release drug preparation - Google Patents
Controlled release drug preparationInfo
- Publication number
- CA1293449C CA1293449C CA000520266A CA520266A CA1293449C CA 1293449 C CA1293449 C CA 1293449C CA 000520266 A CA000520266 A CA 000520266A CA 520266 A CA520266 A CA 520266A CA 1293449 C CA1293449 C CA 1293449C
- Authority
- CA
- Canada
- Prior art keywords
- beads
- metoprolol
- salt
- preparation
- size
- 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.)
- Expired - Lifetime
Links
Abstract
ABSTRACT
Controlled release preparation containing a number of insoluble beads applied with one or more pharmaceutically active compounds, a method for the production thereof and the use in a treatment where a controlled release of a pharmaceutically active compound is needed. Preferred active compounds are salts of metoprolol.
Controlled release preparation containing a number of insoluble beads applied with one or more pharmaceutically active compounds, a method for the production thereof and the use in a treatment where a controlled release of a pharmaceutically active compound is needed. Preferred active compounds are salts of metoprolol.
Description
~3~3 The present invention is related to new pharmaceutical preparations with controlled release of a pharmaceutically active compound, to a method for the manufacture of such preparations and to a method of obtaining controlled release of a pharmaceuti-cally active compound. In a preferred aspect, the invention relates to a new pharmaceutical preparation with controlled release of metoprolol and to a method for treatment of cardio-vascular disorders using the new pharmaceutical preparation con taining metoprolol In the medical treatment of various diseases, e.g. in the cardiovascular, gastrointestinal and chemotherapeutic field, it is an advantage to have a constant concentration of the administered drug in the blood. Thus a controlled release of the drug from the pharmaceutical preparation is wanted.
It is important that the controlled release preparation delivers the amount of drug needed to maintain an adequate and even effect during the entire therapeutic dosage interval~ This usually means that the drug should be delivered at a constant rate to give an even concentration of the administered drug in the blood which is of specific importance for drugs having a small therapeutic index, i.e. a small difference between effective and toxic concen-tration. A delayed and constant release of the drug will also be of importance for locally irritating drugs having a potential risk of causing gastrointestinal disturbances when present in large local concentrations, or for drugs having a short elimination half-life. In the latter case less frequent administration and thus ~334~
better patient compliance (cE. Hayes R.B. et al. Clin. Pharm.
Therap. (1977), 22, p. 125-130) may be obtalned with controlled release preparations compared with conventional dosage ~orms.
A drug can be delivered in a controlled way via any route of administration but the preparations should preferably have some features in common, e.g. give a controlled and reproduc-ible release of drug and contribute to a reproducible absorption, have no toxic or irritating constituents and be suitable also for high dosage drugs.
Examples of drug delivery systems for oral use with a controlled release of the drug are e.g. sustained release tablets of the insoluble matrix type, such as Durules(~), and the osmoti-cally active tablet, OROS(~). The OROS(~) system is described in United States Patent 4 036 ~27 and in a supplement to British Journal of Clinical Pharmacology (1985), 19, 695-765 by Theeuwes F.
et al. It consists of a tablet core of the drug substance as the major constituent which is surrounded with a semipermeable poly-meric membrane through which a small opening is drilled.
DE-A-2030501 describes a preparation of the matrix type which con-tains amorphous silicon dioxide. The active compound is released by dii~fusion through the matrix. The examples above are single-unit systems with all drug substance concentrated in one unit while the present invention is of the multiple-unit principle.
From GB-A-1542414 there is known a composition containing an organic support material to which an active compound is physical-l~r or chemically bound and a glass material in contact with said 2g3~
support material. The glass contains soluble metal ions. The release of drug is governed by the dissolution of metal ions from the glass material due to an ion exchange process. Obviously, the glass is not an insoluble inert compound of the composition.
There are advantages of a depot preparation comprising a large number of small units, each of which releases the drug at a controlled rate over a depot preparation consisting of one single unit, e.g. a matrix tablet or a tablet surrounded by a coating, which controls the release. It is, for example, possible to obtain a reproducible emptying of the units from the stomach into the small intestine when the particles are less than 1-2 mm ~cf.
Bogentoft C. et al: Influence of food on the absorption o~ acetyl-salicylic acid Erom enteric coated dosage forms. Europ. J. Clin.
Pharmacol. ~1978), 14, 351-355). Dispersion over a large area in the gastrointestinal canal can give a more reproducible total time for the passage, which is of advantage for the absorption process (cf. Edgar B. et al: Comparison of two enteric-coated acetylsalicylic acid preparations by monitoring steady-state levels of salicylic acid and its metabolites in plasma and uri~ne. Bio-pharmaceutics & Drug Disposition, (1984)/ 5, 251-260). In addition a multiple unit preparation is preferable to one single drug unit as the dose is spread out in the intestine. The risk of local irritation and accumulation of several doses due to constriction in the alimentary canal are also considered to be lower/ (cf.
McMahan F.G. et al: Upper gastrointestinal lesions after potassium chloride supplements: A controlled clinical trial The Lancet/
~z~ 9 Nov. 13, 1059-1061).
A further advantage with a multiple unit preparation is that it may be divided into smaller portions all having the same absorption properties. This makes it possible to obtain a greater flexibility in selecting the size of the dose.
Metoprolol, which has the structural formula L112CH-C~12NaCa ca3 is known from e.g. DE-2 106 209. The drug, which is a ~-adreno-ceptor antagonist has preferably been used as a saltj e.g. the tartrate.
Metoprolol blocks the adrenergic stimulation of the heart and thus reduces the oxygen demand of the cardiac tissue.
Apparently, this explains its beneficial effects in angina pectoris and cardioprotective action in myocardial infarction. In addition metoprolol normalizes blood pressure in a large proportion of patients with arterial hypertension which probably is dwe to an additional action on the control of peripheral resistance to blood-flow.
For patients suffering from cardiovascular disorders it 2~ is advantageous to have a constant concentration of the administer~
ed drug in the blood. Thus, a controlled release of the drug over a long period of time is desirable. According to the most common treatment, the patients are ordered one fast dissolving tablet 3~
twice a day. This gives a varying concentration with high peak and trough values of the drug during the day.
For dosage once a day metoprolol has been incorporated in controlled release tablets of the insoluble matrix type, e.g.
Durules ~ . However the drug release from the matrix tablets is not satis~ying as about 50 per cent of the dose is released within a few hours after administration. There has thus been a demand to find a way to obtain a drug preparation having a more constant con-trolled release of the active component for approximately 20-24 hours, whereby smoother blood concentration and effect profiles will be obtained over the entire dosage interval.
The above-mentioned drug delivery system Oros ~ may be used to obtain a controlled release of e.g. metoprolol for once daily dosage. Oros ~ is a single-unit system consisting of an osmotically active core composed mainly of the drug substance sur-rounded by a semipermeable membrane through which a single small opening is drilled. The release of the drug from the system remains constant as long as a steady osmotic pressure is maintained across the membrane. 50-60% of the total content of the drug is released at a constant rate.
In SE-A-8400085 it has been proposed to prepare an enteric coated product, containing e.g. metoprolol, and with slow release of the active compound close to the colon. Such a preparation does not give the constant and slow p~I-independent release of metoprolol, which the preparation according to this invention gives.
Depot preparations comprising a large number of smaller , :
units are also known e.g. from ~P 13263. This patent describes ~harmaceutically indifferent cores covered by the active compound.
The cores are made of soluble material e.g. lactose.
The present invention relates to new preparations giving a controlled release of one or mo~e pharmaceutically a~tive compounds.
The present invention provides controlled release beads coated with a membrane controlling drug release characterized in that they contain one or more pharmaceutically active compounds applied on a compact insoluble core material, whereby the active compound forms a compact layer on the insoluble core and this compact layer is ~urther covered with a release controlling polymeric membrane.
The lnvention ~urther provides aontrolled release preparation containing a salt of metoprolol characterized in that the preparation contains a number of beads comprislng a salt of metoprolol as the maln soluble component and that said beads are coated with a polymeric membrane containing derivatives of cellulose without protolysable groups and whereby at least 75% o~
~he dose of metoprolol 1s released within 20 hours virtually independent of the pH ln the interval 1-8.
In one embodiment, the preparation consists of a large number of s~all insoluble particles, i.e. cores, which are covered by a pharmaceutically active compound. The cores have a size of 0.1-2 mm, preferably 0.1-0.5 mm, and conslst of insoluble lnert material. By "insoluble" is meant that the material is not soluble ln water, physiological fluids or in common liquids used ~3~
23940~542 for intravenous infusion. ~xamples of insoluble inert material inalude silicon dioxide, glass and plastic resin particles.
Suitable plastic materials are pharmaaeutically acceptable plastics, such as polypropylene or polyethylene, prefarably polypropylene. The core material should have a standardized size and shape, preferably spherlcal with an even surface. Preferably, the core material should have a density which is sufficiently high to make i~ suitable for a fluidized-bed process. Furthermore, it is important that the core material has a high degree of purity, that is, is free from soluble contamlnating compounds.
The pharmaceutically active compound is applied on the core material preferably by sprayin~ from a solution. The aative compound thereby forms a compact layer on the insoluble aore.
Pharmaceutically active compounds used are those havlng a cardio-- 6a -3~
vascular, gastrointestinal or chemotherapeutic effect, especially adrenergic be~a-blocking agents and antibiotics. Examples of suit-able pharmaceutically active compounds which can be applied on the core material are salts of alprenolol, metoprolol, quinidine, magnesium, and ampicillin. The resulting particles or beads have a size of 0.2-3.0 mm, preferably 0.3-1.0 mm. It is however pos-sible to form controlled release preparations according to the method above for most drugs for which such preparations are wanted, ; provided they can be dissolved in a solvent that can be dried off during processing.
The beads according to the invention are compact, which means that the porosity is less than 15 per cent.
The beads are coated with a poly~eric membrane modiying and controlling the drug release. The polymeric membrane can release the drug according to various release profiles, e.g. pH
dependent, enteric coating, pH independent, with or without lag time. The most important use is pH independent controlled release ; in the range of pH 1-8. Examples o suitable polymeric materials are ethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl phthalate (e.g. HP 55), cellulose acetate phthalate, Eudragit ~ RL, Eudragit ~ RS. Ethyl cellulose can be used alone or in a combination with e.g. a water soluble polymer such as hydroxypropylmethyl cellulose to adjust the per-meability of the coating layer.
Ethyl cellulose is available in grades having different viscosities. In the examples given below, ethyl cellulose _ 7 _ -34'~9 qualitles with a viscosity of 10, 50 or 1~0 cps are used, but also other types of ethyl cellulose are suitable.
Eudragit ~ is the trade name for a number of film coating substances on an acrylic resin basis produced by Rohm Pharma.
E.g. Eudragit RL and RS are copolymers synthesized from acrylic and methacrylic acid esters with a low content of quaternary ammon-ium groups. The molar ratio of these ammonium groups to the remaining neutral (meth)acrylic acid esters is 1:20 for Eudragit RL and 1:40 for Eudragit ~ RS, resulting in different permeability characteristics. Other variants of Eudragit that can be used are Eudragit L, Eudragit S and Eudragit E.
Pigments and/or plasticizers may be added to the poly-meric solution in order to improve the technical properties of the membrane or modify the release characteristics. Examples of plasticizers that may be used are citrate esters, acetylated mono-glycerides, and glycerinetriacetate.
The new preparation has several advantages, e.g. the par-ticles contain a high percentage of active ingredient and are not contaminated by soluble inert compounds, which is the case, when cores o e.g. lactose or sugar are covered by a therapeutically act.ive compound. This is especially important when the preparation is used for parenteral adminis-tration.
By using small dense particles of e.g. silicon dioxide as the core material, it is possible to obtain highly concentrated beads (granules) of the active compound which is an advantage ror high dosage preparations, e.g. magnesium chloride.
.....
:~939L~
An advantage with the new preparation is that in ~eneral less polymeric material is needed to obtain a delayed drug release when the insoluble cores applied with an active compound are coated compared to when preparations having a soluble core material are coated, as is demonstrated below~ The preparation according to -the invention can be administered by various routes, e.g. orally or parenterally. An example of intravenous administration is via the drug-administration-device described in EP-Bl-59694.
When using the coated beads of active compound according to this invention for oral application, it is possible to formul-ate the preparation as granules filled into hard gelatine capsules,filled into sachets or formed into tablets and still obtain the desired plasma concentration profile and duration of the effect after administration.
;When the small beads are tabletted they are mixed with additives containing e.g. microcrystalline cellulose, such as Avicel ~, which improves the tabletting properties and facilitates the disintegration of the tablet to liberate the individual beads.
The invention makes it possible to obtain a decreased 2~ dosing frequency and still have an almost constant concentration of the drug in the plasma during the whole period until the next dose is administered. A single dose a day is often sufficlent with the new preparation.
A process for the manufacture of a controlled release pre-paration represents a further aspect of the invention. The pharma-ceutically active compound is dissolved in a suitable solvent e.g.
: _ 9 .~
~.Z93~
methylene chloride, ethanol, isopropylic alcohol or water and sprayed onto the insoluble core material in a coating pan or pre-ferably in a fluidized bed and the solvent is dried off. The beads obtained are then coated with a polymeric layer described above.
The polymeric mixture is dissolved in a solvent such as ethanol, isopropyl alcohol and/or methylene chlorideO The spraying can be carried out in a coating pan, but is preferably carried out in a fluidized bed. Ethyl cellulose can also be applied from an aqueous dispersion (latex).
The preparation according to the invention is particular-ly advantageous when a controlled and constant release oE a thera-peutically active compound is wanted. A method ~or the controlled release of therapeutically active compounds represents a further aspect of the invention.
In a preferred aspect, the present invention relates to ;~ a preparation containing metoprolol as active ingredient and having ~ a controlled rate of drug release during at least 15 hours. By i making a preparation containing a large number of small compact particles all comprising a salt of metoprolol as the main soluble component and coated with a polymeric membrane containing deriva-tives of cellulose without protolysable groups it has been possible to prepare a suitable dosage form having a controlled rate of release of metoprolol, virtually independent of pH, during 16-24 ; hours. The small particles, beads, containing metoprolol have a size of 0.25-2 mm, preferably 0.35-1.0 mm.
.
, . -- 10 --.
~LZ93~ ~9 The beads may contaln metoprolol alone or may consist of insoluble cores coated with metoprolol. The beads have a very high content of metoprolol, preferably 95-100 w/w~ of the soluble part of the beads. The insoluble cores have a size of 0.1-1.0 mm, preferably 0.15-0.3 mm. Examples of insoluble cores according to the invention are silicon dioxide and small particles of glass.
The beads according to the invention are compact, which means that their porosity is less than 15 per cent.
As can be seen from Examples below, a new preparation is characterized in that at least 75% of the metoprolol is released within 20 hours and at least 50% of the dose of metoprolol is released at khe rate 3-7 w/w %/hour.
Metoprolol used in the preparation may be in the form of the racemate, or one of the enantiomers, namely the S-isomer.
(Preferably, the concentration of the S-isomer should be at least 95~ in relation to the R-form.) Suitable soluble salts of metoprolol have a solubility less than 600 mg/ml in water at 25C, preferably 30-6Q0 mg/ml in water at 25C. Examples of suitable salts are salts formed with organic carboxylic acids, preferably of low molecular weight. Es-pecially preferred are the succinate, fumarate or benzoate or racemic metoprolol and the benzoate or sorbate of the S-enantiomer of metoprolol. Very soluble salts, e.g. tartrate, hydrochloride are less suitable according to the present invention.
Examples of suitable polymeric materials are ethyl cellulose or a mixture of ethyl cellulose with hydroxypropylmethyl ~:
. . ~ . .
:~Z~33~
cellulose, hydroxypropyl cellulose, Eudragit RL or Eudragit RS.
Ethyl cellulose is available in variants having different grades of viscosity. According to the invention it is suitable to use ethyl cellulose having a viscosity between 10-50 cps, but also other types of ethyl cellulose may be used.
Plasticizers and/or pigments may be added to the polymeric layer in order to improve the technical properties of the layer or change the permeability of the coating. Examples of suitable plasticizers are citrate esters, acetylated monoglycerides and glycerinetriacetate; especially preferred is acetyltributylcitrate.
The polymeric membrane is made of one or more polymers and gives a membrane with virtually pH-independent permeability characteristics within the pH range 1.0-8Ø
Each coated bead of metoprolol according to this inven-tion forms an individual controlled release unit, releasing the drug at a predetermined rate. Therefore, the coated beads accord-ing to this invention make it possible to formulate and administer the preparation in di~ferent dosage forms. They can be filled into e.g. hard gelatin capsules or sachets or compressed to tablets and 2Q still give the desired plasma concentration profile and duration of the effect.
When the small coated particles of metoprolol are tabletted they are mixed with additives e.g. microcrystalline cellu-lose such as Avicel ~, which improves the tabletting properties and facilitates the disintegration of the tablet, whereby the individual beads are liberated.
~93~
The invention makes it possible to formulate pharmaceuti-cal dosage forms which can be given once daily and still produce almost constant concentrations of the drug in the blood during the entire dosage interval until the next dose is administered.
A process for the manufacture of the controlled release preparation containing metoprolol represents a further aspect of the invention. After the initial forming of the beads containing metoprolol, the beads obtained are coated with the polymeric layer described in the examples. The polymeric mixture is dissolved in an organic solvent such as ethanol, isopropyl alcohol and/or methylene chloride. The spraying can be carried out in a coating pan, but is preferably carried out in a fluidi~ed bed. Ethyl cellulose can also be applied from an aqueous dispersion (latex).
; The preparation containing metoprolol according to the invention is particularly advantageous in the treatment of cardio-vascular disorders, and a method for the treatment of such condi-tions represents a further aspect of the invention.
The invention is described in detail in the following examples and with reference to the accompanying drawings.
In the accompanying drawings, Figure 1 is a graph showing cumulative release of active compound over time, using different core materials;
Figure 2 is a graph showing cumulative release of active compound over time, using a potassium chloride core~
Figure 3 is a graph showing plasma concentration of metoprolol over time, after single dose administration;
~3~
Figure 4 is a graph showingin vitro release of meto-prolol over time;
Figure 5 is a graph showing reduction of heart rate following administration of metoprolol.
EXAMPLES
Example 1 Cores Metoprolol fumarate 1440 g Methylene chloride 9618 g Ethanol 95% 3888 g SiO2 (0.15-0.25 mm) 375 g .:
9 3 9~3 Polymeric layer Ethyl cellulose 10 cps265.6 g Hydroxypropylmethyl cellulose 58.4 9 : 5 Acetyltributylcitrate 36.0 g Methylene chloride 6141 g Isopropylic alcohol 1544 9 In a fluidized bed granulator metoprolol fumarate was sprayed onto the cores of silicon dioxide from a solution of ethanol 95%. 4Q0 9 of the beads so formed (fraction 0.4-0.63 mmj were covered with the polymeric solution containing ethyl cellulose 10 cps, hydroxypropylmethyl : cellulose and acetyltributylcitrate by spraying a solution of the mentioned substances in methylene chloride and isopropylic alcohol.
15 The coated beads were then filled into hard gelatine capsules.
Examples 2-3 and Reference 1 Cores 2 3 Reference 1 Metoprolol succinate 1440 9 1440 9 1440 9 Methylene chloride 9618 g 9618 9 9618 9 i Ethanol 95% 3888 9 3888 9 3888 9 SiO2 (0.15-0.25 mm) 375 9 Glass (0.2 mm) 375 9 NaCl (0.15-0.25 mm) 375 g Polymeric layer 400 9 of the granules (fraction 0.4-0.5 mm) above were coated with a composition comprising : Ethyl cellulose 10 cps 52.3 9 Acetyltributylcitrate 8.6 9 -~ 35 Methylene chloride 1111 9 Isopropylic alcohol 218 9 .
", ~93~
Metoprolol succinate was sprayed onto the cores of silicon dioxide, glass and sodium chloride, respectively, from a solution of ethanol 95% and methylene chloride. The beads so formed were coated with the polymeric solution containing ethyl cellulose 10 cps and acetyltributyl-5 citrate dissolved in methylene chloride and isopropylic alcohol by spray-ing. Figure 1 illustrates the cumulative release of metoprolol succinate during 20 hours. As can-be seen from the figure a controlled and almost constant release of the active compound was obtained, when the active compound was applied on silicon dioxide or glass, whereas a core of 10 soluble sodium chloride resulted in a considerably higher initial release rate, which also is illustrated in Figure 2 (Reference 2 below) where soluble potassium chloride was used as core material.
eference 2 Cores Metoprolol succinate 2000 g KCl (0.1-0.2mm) 400 9 Methylene chloride13360 9 Ethanol 95% 7900 9 400 9 of the granules according to Reference 2 were coated with a compo-sition comprising Polymeric layer Ethyl cellulose 10 cps 135.3 9 Eudragit(~)RS 27.4 g Acetyltributylcitrate 27.4 9 Methylene chloride4469 9 Isopropylic alcohol661 9 The granules were formulated as described in the previous examples.
.. , '' .. , - - . .........
Examples 4-6 Cores Example ; 5 Metoprolol succinate l440 91440 g 1440 9 Methylene chloride 9618 99618 9 9618 9 Ethanol 95% 3888 93888 9 3888 9 SiO2 (0.15-0.2 mm) 375 9 ; SiO2 (0.25-0.3 mm) 375 9 SiO2 (0.4-0.5 mm) 375 9 400 9 of the granules according to Examples 4-6 were coated with a composition comprising Polymeric layer granulate according to Example Ethyl cellulose 10 cps 187.2 9144.0 9 92.2 9 Hydroxypropylmethyl cellulose46.8 936.0 9 23.0 9 Acetyltributylcitrate 26.0 g20.0 9 12.8 9 Methylene chloride 4428 93408 9 2168 9 Isopropylic alcohol 1114 9 858 9 546 9 The preparations were formulated as described above. In the enclosed Table 1 the release of metoprolol succinate during 20 hours is given.
; All preparations gave a controlled release of drug during a long period of time.
Example 7 Cores Magnesium chloride, hexahydrate 1100 g Ethanol 99.5% 6200 9 Silicon dioxide (0.15-0.30 mm)400 9 - l7 ~
:' .
.. .
Z5~3 Polymerlc layer Ethyl cellulose 50 cps 533 9 Methylene chloride 14107 9 Isopropylic alcohol 5481 9 Magnesium chloride ~MgC12) was sprayed onto the cores of silicon dioxide from a solution of ethanol 99.5%. 400 9 of the beads so formed were coated with ethyl cellulose 50 cps from a solution of methylene chloride and isopropylic alcohol to give granules containing 34? mg/g~magnesium chloride (MgC12). The in vitro release of drug (magnesium chloride) was 38% after 1 hour, 58~ after 2 hours and 82 after 6 hours.
Example 8 Cores --.
Ampicillin - Na 600 9 Ethanol 95% 894 9 ~` 20 Water purified 1020 9 Glass (0.5 mm) 500 9 Polymeric layer ~, Ethyl cellulose 100 cps 15 9 Methylene chloride 600 9 Isopropylic alcohol 150 9 Ampicillin-Na was sprayed onto the cores of glass from the ethanol/water solution. 500 9 of the ampicillin-Na beads were then coated with a poly-meric solution of ethyl cellulose 100 cps in methylene chloride/isopro-pylic alcohol. After 40 minutes in vitro dissolution 50% of the drug content was released from the beads.
- 1~
3~f~
Example 9 Cores . 5 Metoprolol succinate 1440 9 Methylene chloride 9618 9 Ethanol 95% 3888 9 SiO2 (0.15-0.25 mm) 375 9 ~ lO Polymeric layer : Ethyl cellulose N-lO 166.2 9 Hydroxypropylmethyl cellulose39.0 g Acetyltributylcitrate 22.8 9 Methylene chloride 3889 9 Tsopropylic alcohol 978 9 Tablet additives Microcrystalline cellulose429.3 9 ' Corn starch 67.1 9 Lactose powder 40-3 9 Polyvidone 55.5 9 ~ Water purified 314.7 9 : 25 Magnesium stearate 1.2 9 Tablet coating ~12.500 tablets) Hydroxypropylmethyl cellulose 6 cps 159.6 9 Polyethylene glycol 6000 39.9 9 Colour Titanium Dioxide 39.9 9 Water purified 1356 9 Paraffin 1 . 6 9 : ~`
Metoprolol succinate was sprayed onto the cores of silicon dioxide according to the process described in the previous examples. 400 9 of the so obtained beads (~raction 0.4-0.63 mm) were coated with the poly-:~
meric solution described aboveO The coated beads of metoprolol succinate were mixed with the additives in equal portions and after addition of Mg-stearate 0.1%, the dry mixture was compressed to tablets. Finally, the tablets were coated :Ln a coating pan with the polymeric solution described above.
The very small particles, 0.15-0.25 mm, of dense SiO2 used as the core material, contribute to a high content of drug in the small beads formed (O.4-0.63 mm) and thus to a reduced size of the final preparation.
Example 10 Metoprolol succinate 1440 g Methylene chloride 9618 g Ethanol 95% 3888 g SiO2 (0.15-0.25 mm) 375 g Polymeric layer -Ethyl cellulose 50 cps 168.1 g Hydroxypropylmethyl cellulose36.9 g Acetyltributylcitrate 22.8 g Methylene chloride 4167 g Isopropylic alcohol 815 g Tablet additives Microcrystalline cellulose470.3 g Maize starch 117.6 g Potato starch 10.5 g Water purified 342.2 g Magnesium stearate 1.2 g -- ~,0 --~ ~ ~93g~4~
Metoprolol succinate was sprayed onto the cores of sili-con dioxide according to the process described in Example l. 400 g of the granules so formed were coated with a polymeric film con-taining ethyl cellulose 50 cps, hydroxypropylmethyl cel]ulose and acetyltributylcitrate. An additional tablet mass was maae by wet granulation of the dry mixture of microcrystalline cellulose and maize starch with the potato starch-water solution in a planetary mixer. Equal amounts (600 g) of the active and additional granules were finally mixed with Mg-stearate 0.1~ and compressed to tablets.
Example 11 This example illustrates an embodiment of the invention in which the core is composed only of a salt of metoprolol; no insoluble core is present. Metoprolol succinate lO0~ in the form of compact spherical granules and having an average particle size of 0.42 mm.
400 g of the metoprolol succinate granules above of particles less than 0.63 mm were coated with Ethyl cellulose lO cps177.1 g ~ydroxypropylmethyl cellulose 38.9 g Acetyltributylcitrate 24.0 g Methylene chloride 4094 g Isopropylic alcohol 10~9 g The beads obtained were formed into pharmaceutical pre-parations as described above.
Example 12 S-enantiomeric metoprolol sorbate in the form of compact spherical granules in the fraction 0.4-0.63 mm.
~, 939L'~
40 g of the metoprolol sorbate granules above with par-ticles less than 0.63 mm together with 360 g of non-pareil granules with particles between 0.75-1.0 mm were coated with ; Ethyl cellulose 10 cps51.7 g Hydroxypropylmethyl cellulose 11.3 g Acetyltributylcitrate 7.0 g Methylene chloride 1194 g Isopropylic alcohol 300 g The beads obtained were formed into pharmaceutical pre-parations as described above.
Table 1 summarizes the drug release data for the composi-tions according to examples 1-6 and 9 and ReEerence examples 1 and .
Biopharmaceutical studies An oral application of the present invention (Example 9) is illustrated in Figure 3. The multiple-unit system was applied on metoprolol succinate in order to find a preparation for dosage once daily with an even plasma concentration profile over 24 hours.
A single dose of 190 mg metoprolol succinate (e~uivalent to 200 mg metoprolol tartrate) in a controlled release preparation according to the present invention was administered to 10 healthy male subjects. The plasma concentrations of metoprolol were com-pared with the plasma concentrations after a single dose of a sustained release tablet (Durules ~ ) based on the insoluble matrix principle containing 200 mg of metoprolol tartrate. Each point represents the mean data from the 10 subjects. As can be seen the 3 3 f~ L~
preparation according to the invention gave an almost constant plasma concentration profile of metoprolol, whereas the matrix tablet gave an unwanted high peak in the plasma concentration dur-ing the first hours after the administration.
Reduction of exercise heart rate 12 subjects were given an ordinary tablet containing lOO
mg of metoprolol tartrate once a day and the reduction of the exercise heart rate on day 5 of the treatment was measured and com-pared with the reduction of the exercise heart rate on day 5 in subjects given a controlled release preparation according to Example 9 of the invention containing 95 mg metoprolol succinate (equivalent to lOO mg metoprolol ta~trate). The reduction of the heart rate i5 illustrated in ~igure 5. As can be seen, the pre-paration according to the invention gives an even pharmacodynamic effect for 24 hours.
The best mode of carrying out the invention is at present considered to be Example 9.
- 23 _ . .
34~
o O , o~ N O C~
0~ ~ $ 0~_ O d' C~) eJ N
OD ~ C~'l 1` 0 . 00 ~' s I~
E cn ~ I o~ J N N C~
0~ ~ ~ C~
~D ~
O ~ r) ~ O ~ C~l a) ~- 11~ U~ ~D ~ 1~ ~ d- et LO
a~ 0~ cn ~ ~ co ~ ~ o~ ~ ~
It is important that the controlled release preparation delivers the amount of drug needed to maintain an adequate and even effect during the entire therapeutic dosage interval~ This usually means that the drug should be delivered at a constant rate to give an even concentration of the administered drug in the blood which is of specific importance for drugs having a small therapeutic index, i.e. a small difference between effective and toxic concen-tration. A delayed and constant release of the drug will also be of importance for locally irritating drugs having a potential risk of causing gastrointestinal disturbances when present in large local concentrations, or for drugs having a short elimination half-life. In the latter case less frequent administration and thus ~334~
better patient compliance (cE. Hayes R.B. et al. Clin. Pharm.
Therap. (1977), 22, p. 125-130) may be obtalned with controlled release preparations compared with conventional dosage ~orms.
A drug can be delivered in a controlled way via any route of administration but the preparations should preferably have some features in common, e.g. give a controlled and reproduc-ible release of drug and contribute to a reproducible absorption, have no toxic or irritating constituents and be suitable also for high dosage drugs.
Examples of drug delivery systems for oral use with a controlled release of the drug are e.g. sustained release tablets of the insoluble matrix type, such as Durules(~), and the osmoti-cally active tablet, OROS(~). The OROS(~) system is described in United States Patent 4 036 ~27 and in a supplement to British Journal of Clinical Pharmacology (1985), 19, 695-765 by Theeuwes F.
et al. It consists of a tablet core of the drug substance as the major constituent which is surrounded with a semipermeable poly-meric membrane through which a small opening is drilled.
DE-A-2030501 describes a preparation of the matrix type which con-tains amorphous silicon dioxide. The active compound is released by dii~fusion through the matrix. The examples above are single-unit systems with all drug substance concentrated in one unit while the present invention is of the multiple-unit principle.
From GB-A-1542414 there is known a composition containing an organic support material to which an active compound is physical-l~r or chemically bound and a glass material in contact with said 2g3~
support material. The glass contains soluble metal ions. The release of drug is governed by the dissolution of metal ions from the glass material due to an ion exchange process. Obviously, the glass is not an insoluble inert compound of the composition.
There are advantages of a depot preparation comprising a large number of small units, each of which releases the drug at a controlled rate over a depot preparation consisting of one single unit, e.g. a matrix tablet or a tablet surrounded by a coating, which controls the release. It is, for example, possible to obtain a reproducible emptying of the units from the stomach into the small intestine when the particles are less than 1-2 mm ~cf.
Bogentoft C. et al: Influence of food on the absorption o~ acetyl-salicylic acid Erom enteric coated dosage forms. Europ. J. Clin.
Pharmacol. ~1978), 14, 351-355). Dispersion over a large area in the gastrointestinal canal can give a more reproducible total time for the passage, which is of advantage for the absorption process (cf. Edgar B. et al: Comparison of two enteric-coated acetylsalicylic acid preparations by monitoring steady-state levels of salicylic acid and its metabolites in plasma and uri~ne. Bio-pharmaceutics & Drug Disposition, (1984)/ 5, 251-260). In addition a multiple unit preparation is preferable to one single drug unit as the dose is spread out in the intestine. The risk of local irritation and accumulation of several doses due to constriction in the alimentary canal are also considered to be lower/ (cf.
McMahan F.G. et al: Upper gastrointestinal lesions after potassium chloride supplements: A controlled clinical trial The Lancet/
~z~ 9 Nov. 13, 1059-1061).
A further advantage with a multiple unit preparation is that it may be divided into smaller portions all having the same absorption properties. This makes it possible to obtain a greater flexibility in selecting the size of the dose.
Metoprolol, which has the structural formula L112CH-C~12NaCa ca3 is known from e.g. DE-2 106 209. The drug, which is a ~-adreno-ceptor antagonist has preferably been used as a saltj e.g. the tartrate.
Metoprolol blocks the adrenergic stimulation of the heart and thus reduces the oxygen demand of the cardiac tissue.
Apparently, this explains its beneficial effects in angina pectoris and cardioprotective action in myocardial infarction. In addition metoprolol normalizes blood pressure in a large proportion of patients with arterial hypertension which probably is dwe to an additional action on the control of peripheral resistance to blood-flow.
For patients suffering from cardiovascular disorders it 2~ is advantageous to have a constant concentration of the administer~
ed drug in the blood. Thus, a controlled release of the drug over a long period of time is desirable. According to the most common treatment, the patients are ordered one fast dissolving tablet 3~
twice a day. This gives a varying concentration with high peak and trough values of the drug during the day.
For dosage once a day metoprolol has been incorporated in controlled release tablets of the insoluble matrix type, e.g.
Durules ~ . However the drug release from the matrix tablets is not satis~ying as about 50 per cent of the dose is released within a few hours after administration. There has thus been a demand to find a way to obtain a drug preparation having a more constant con-trolled release of the active component for approximately 20-24 hours, whereby smoother blood concentration and effect profiles will be obtained over the entire dosage interval.
The above-mentioned drug delivery system Oros ~ may be used to obtain a controlled release of e.g. metoprolol for once daily dosage. Oros ~ is a single-unit system consisting of an osmotically active core composed mainly of the drug substance sur-rounded by a semipermeable membrane through which a single small opening is drilled. The release of the drug from the system remains constant as long as a steady osmotic pressure is maintained across the membrane. 50-60% of the total content of the drug is released at a constant rate.
In SE-A-8400085 it has been proposed to prepare an enteric coated product, containing e.g. metoprolol, and with slow release of the active compound close to the colon. Such a preparation does not give the constant and slow p~I-independent release of metoprolol, which the preparation according to this invention gives.
Depot preparations comprising a large number of smaller , :
units are also known e.g. from ~P 13263. This patent describes ~harmaceutically indifferent cores covered by the active compound.
The cores are made of soluble material e.g. lactose.
The present invention relates to new preparations giving a controlled release of one or mo~e pharmaceutically a~tive compounds.
The present invention provides controlled release beads coated with a membrane controlling drug release characterized in that they contain one or more pharmaceutically active compounds applied on a compact insoluble core material, whereby the active compound forms a compact layer on the insoluble core and this compact layer is ~urther covered with a release controlling polymeric membrane.
The lnvention ~urther provides aontrolled release preparation containing a salt of metoprolol characterized in that the preparation contains a number of beads comprislng a salt of metoprolol as the maln soluble component and that said beads are coated with a polymeric membrane containing derivatives of cellulose without protolysable groups and whereby at least 75% o~
~he dose of metoprolol 1s released within 20 hours virtually independent of the pH ln the interval 1-8.
In one embodiment, the preparation consists of a large number of s~all insoluble particles, i.e. cores, which are covered by a pharmaceutically active compound. The cores have a size of 0.1-2 mm, preferably 0.1-0.5 mm, and conslst of insoluble lnert material. By "insoluble" is meant that the material is not soluble ln water, physiological fluids or in common liquids used ~3~
23940~542 for intravenous infusion. ~xamples of insoluble inert material inalude silicon dioxide, glass and plastic resin particles.
Suitable plastic materials are pharmaaeutically acceptable plastics, such as polypropylene or polyethylene, prefarably polypropylene. The core material should have a standardized size and shape, preferably spherlcal with an even surface. Preferably, the core material should have a density which is sufficiently high to make i~ suitable for a fluidized-bed process. Furthermore, it is important that the core material has a high degree of purity, that is, is free from soluble contamlnating compounds.
The pharmaceutically active compound is applied on the core material preferably by sprayin~ from a solution. The aative compound thereby forms a compact layer on the insoluble aore.
Pharmaceutically active compounds used are those havlng a cardio-- 6a -3~
vascular, gastrointestinal or chemotherapeutic effect, especially adrenergic be~a-blocking agents and antibiotics. Examples of suit-able pharmaceutically active compounds which can be applied on the core material are salts of alprenolol, metoprolol, quinidine, magnesium, and ampicillin. The resulting particles or beads have a size of 0.2-3.0 mm, preferably 0.3-1.0 mm. It is however pos-sible to form controlled release preparations according to the method above for most drugs for which such preparations are wanted, ; provided they can be dissolved in a solvent that can be dried off during processing.
The beads according to the invention are compact, which means that the porosity is less than 15 per cent.
The beads are coated with a poly~eric membrane modiying and controlling the drug release. The polymeric membrane can release the drug according to various release profiles, e.g. pH
dependent, enteric coating, pH independent, with or without lag time. The most important use is pH independent controlled release ; in the range of pH 1-8. Examples o suitable polymeric materials are ethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl phthalate (e.g. HP 55), cellulose acetate phthalate, Eudragit ~ RL, Eudragit ~ RS. Ethyl cellulose can be used alone or in a combination with e.g. a water soluble polymer such as hydroxypropylmethyl cellulose to adjust the per-meability of the coating layer.
Ethyl cellulose is available in grades having different viscosities. In the examples given below, ethyl cellulose _ 7 _ -34'~9 qualitles with a viscosity of 10, 50 or 1~0 cps are used, but also other types of ethyl cellulose are suitable.
Eudragit ~ is the trade name for a number of film coating substances on an acrylic resin basis produced by Rohm Pharma.
E.g. Eudragit RL and RS are copolymers synthesized from acrylic and methacrylic acid esters with a low content of quaternary ammon-ium groups. The molar ratio of these ammonium groups to the remaining neutral (meth)acrylic acid esters is 1:20 for Eudragit RL and 1:40 for Eudragit ~ RS, resulting in different permeability characteristics. Other variants of Eudragit that can be used are Eudragit L, Eudragit S and Eudragit E.
Pigments and/or plasticizers may be added to the poly-meric solution in order to improve the technical properties of the membrane or modify the release characteristics. Examples of plasticizers that may be used are citrate esters, acetylated mono-glycerides, and glycerinetriacetate.
The new preparation has several advantages, e.g. the par-ticles contain a high percentage of active ingredient and are not contaminated by soluble inert compounds, which is the case, when cores o e.g. lactose or sugar are covered by a therapeutically act.ive compound. This is especially important when the preparation is used for parenteral adminis-tration.
By using small dense particles of e.g. silicon dioxide as the core material, it is possible to obtain highly concentrated beads (granules) of the active compound which is an advantage ror high dosage preparations, e.g. magnesium chloride.
.....
:~939L~
An advantage with the new preparation is that in ~eneral less polymeric material is needed to obtain a delayed drug release when the insoluble cores applied with an active compound are coated compared to when preparations having a soluble core material are coated, as is demonstrated below~ The preparation according to -the invention can be administered by various routes, e.g. orally or parenterally. An example of intravenous administration is via the drug-administration-device described in EP-Bl-59694.
When using the coated beads of active compound according to this invention for oral application, it is possible to formul-ate the preparation as granules filled into hard gelatine capsules,filled into sachets or formed into tablets and still obtain the desired plasma concentration profile and duration of the effect after administration.
;When the small beads are tabletted they are mixed with additives containing e.g. microcrystalline cellulose, such as Avicel ~, which improves the tabletting properties and facilitates the disintegration of the tablet to liberate the individual beads.
The invention makes it possible to obtain a decreased 2~ dosing frequency and still have an almost constant concentration of the drug in the plasma during the whole period until the next dose is administered. A single dose a day is often sufficlent with the new preparation.
A process for the manufacture of a controlled release pre-paration represents a further aspect of the invention. The pharma-ceutically active compound is dissolved in a suitable solvent e.g.
: _ 9 .~
~.Z93~
methylene chloride, ethanol, isopropylic alcohol or water and sprayed onto the insoluble core material in a coating pan or pre-ferably in a fluidized bed and the solvent is dried off. The beads obtained are then coated with a polymeric layer described above.
The polymeric mixture is dissolved in a solvent such as ethanol, isopropyl alcohol and/or methylene chlorideO The spraying can be carried out in a coating pan, but is preferably carried out in a fluidized bed. Ethyl cellulose can also be applied from an aqueous dispersion (latex).
The preparation according to the invention is particular-ly advantageous when a controlled and constant release oE a thera-peutically active compound is wanted. A method ~or the controlled release of therapeutically active compounds represents a further aspect of the invention.
In a preferred aspect, the present invention relates to ;~ a preparation containing metoprolol as active ingredient and having ~ a controlled rate of drug release during at least 15 hours. By i making a preparation containing a large number of small compact particles all comprising a salt of metoprolol as the main soluble component and coated with a polymeric membrane containing deriva-tives of cellulose without protolysable groups it has been possible to prepare a suitable dosage form having a controlled rate of release of metoprolol, virtually independent of pH, during 16-24 ; hours. The small particles, beads, containing metoprolol have a size of 0.25-2 mm, preferably 0.35-1.0 mm.
.
, . -- 10 --.
~LZ93~ ~9 The beads may contaln metoprolol alone or may consist of insoluble cores coated with metoprolol. The beads have a very high content of metoprolol, preferably 95-100 w/w~ of the soluble part of the beads. The insoluble cores have a size of 0.1-1.0 mm, preferably 0.15-0.3 mm. Examples of insoluble cores according to the invention are silicon dioxide and small particles of glass.
The beads according to the invention are compact, which means that their porosity is less than 15 per cent.
As can be seen from Examples below, a new preparation is characterized in that at least 75% of the metoprolol is released within 20 hours and at least 50% of the dose of metoprolol is released at khe rate 3-7 w/w %/hour.
Metoprolol used in the preparation may be in the form of the racemate, or one of the enantiomers, namely the S-isomer.
(Preferably, the concentration of the S-isomer should be at least 95~ in relation to the R-form.) Suitable soluble salts of metoprolol have a solubility less than 600 mg/ml in water at 25C, preferably 30-6Q0 mg/ml in water at 25C. Examples of suitable salts are salts formed with organic carboxylic acids, preferably of low molecular weight. Es-pecially preferred are the succinate, fumarate or benzoate or racemic metoprolol and the benzoate or sorbate of the S-enantiomer of metoprolol. Very soluble salts, e.g. tartrate, hydrochloride are less suitable according to the present invention.
Examples of suitable polymeric materials are ethyl cellulose or a mixture of ethyl cellulose with hydroxypropylmethyl ~:
. . ~ . .
:~Z~33~
cellulose, hydroxypropyl cellulose, Eudragit RL or Eudragit RS.
Ethyl cellulose is available in variants having different grades of viscosity. According to the invention it is suitable to use ethyl cellulose having a viscosity between 10-50 cps, but also other types of ethyl cellulose may be used.
Plasticizers and/or pigments may be added to the polymeric layer in order to improve the technical properties of the layer or change the permeability of the coating. Examples of suitable plasticizers are citrate esters, acetylated monoglycerides and glycerinetriacetate; especially preferred is acetyltributylcitrate.
The polymeric membrane is made of one or more polymers and gives a membrane with virtually pH-independent permeability characteristics within the pH range 1.0-8Ø
Each coated bead of metoprolol according to this inven-tion forms an individual controlled release unit, releasing the drug at a predetermined rate. Therefore, the coated beads accord-ing to this invention make it possible to formulate and administer the preparation in di~ferent dosage forms. They can be filled into e.g. hard gelatin capsules or sachets or compressed to tablets and 2Q still give the desired plasma concentration profile and duration of the effect.
When the small coated particles of metoprolol are tabletted they are mixed with additives e.g. microcrystalline cellu-lose such as Avicel ~, which improves the tabletting properties and facilitates the disintegration of the tablet, whereby the individual beads are liberated.
~93~
The invention makes it possible to formulate pharmaceuti-cal dosage forms which can be given once daily and still produce almost constant concentrations of the drug in the blood during the entire dosage interval until the next dose is administered.
A process for the manufacture of the controlled release preparation containing metoprolol represents a further aspect of the invention. After the initial forming of the beads containing metoprolol, the beads obtained are coated with the polymeric layer described in the examples. The polymeric mixture is dissolved in an organic solvent such as ethanol, isopropyl alcohol and/or methylene chloride. The spraying can be carried out in a coating pan, but is preferably carried out in a fluidi~ed bed. Ethyl cellulose can also be applied from an aqueous dispersion (latex).
; The preparation containing metoprolol according to the invention is particularly advantageous in the treatment of cardio-vascular disorders, and a method for the treatment of such condi-tions represents a further aspect of the invention.
The invention is described in detail in the following examples and with reference to the accompanying drawings.
In the accompanying drawings, Figure 1 is a graph showing cumulative release of active compound over time, using different core materials;
Figure 2 is a graph showing cumulative release of active compound over time, using a potassium chloride core~
Figure 3 is a graph showing plasma concentration of metoprolol over time, after single dose administration;
~3~
Figure 4 is a graph showingin vitro release of meto-prolol over time;
Figure 5 is a graph showing reduction of heart rate following administration of metoprolol.
EXAMPLES
Example 1 Cores Metoprolol fumarate 1440 g Methylene chloride 9618 g Ethanol 95% 3888 g SiO2 (0.15-0.25 mm) 375 g .:
9 3 9~3 Polymeric layer Ethyl cellulose 10 cps265.6 g Hydroxypropylmethyl cellulose 58.4 9 : 5 Acetyltributylcitrate 36.0 g Methylene chloride 6141 g Isopropylic alcohol 1544 9 In a fluidized bed granulator metoprolol fumarate was sprayed onto the cores of silicon dioxide from a solution of ethanol 95%. 4Q0 9 of the beads so formed (fraction 0.4-0.63 mmj were covered with the polymeric solution containing ethyl cellulose 10 cps, hydroxypropylmethyl : cellulose and acetyltributylcitrate by spraying a solution of the mentioned substances in methylene chloride and isopropylic alcohol.
15 The coated beads were then filled into hard gelatine capsules.
Examples 2-3 and Reference 1 Cores 2 3 Reference 1 Metoprolol succinate 1440 9 1440 9 1440 9 Methylene chloride 9618 g 9618 9 9618 9 i Ethanol 95% 3888 9 3888 9 3888 9 SiO2 (0.15-0.25 mm) 375 9 Glass (0.2 mm) 375 9 NaCl (0.15-0.25 mm) 375 g Polymeric layer 400 9 of the granules (fraction 0.4-0.5 mm) above were coated with a composition comprising : Ethyl cellulose 10 cps 52.3 9 Acetyltributylcitrate 8.6 9 -~ 35 Methylene chloride 1111 9 Isopropylic alcohol 218 9 .
", ~93~
Metoprolol succinate was sprayed onto the cores of silicon dioxide, glass and sodium chloride, respectively, from a solution of ethanol 95% and methylene chloride. The beads so formed were coated with the polymeric solution containing ethyl cellulose 10 cps and acetyltributyl-5 citrate dissolved in methylene chloride and isopropylic alcohol by spray-ing. Figure 1 illustrates the cumulative release of metoprolol succinate during 20 hours. As can-be seen from the figure a controlled and almost constant release of the active compound was obtained, when the active compound was applied on silicon dioxide or glass, whereas a core of 10 soluble sodium chloride resulted in a considerably higher initial release rate, which also is illustrated in Figure 2 (Reference 2 below) where soluble potassium chloride was used as core material.
eference 2 Cores Metoprolol succinate 2000 g KCl (0.1-0.2mm) 400 9 Methylene chloride13360 9 Ethanol 95% 7900 9 400 9 of the granules according to Reference 2 were coated with a compo-sition comprising Polymeric layer Ethyl cellulose 10 cps 135.3 9 Eudragit(~)RS 27.4 g Acetyltributylcitrate 27.4 9 Methylene chloride4469 9 Isopropylic alcohol661 9 The granules were formulated as described in the previous examples.
.. , '' .. , - - . .........
Examples 4-6 Cores Example ; 5 Metoprolol succinate l440 91440 g 1440 9 Methylene chloride 9618 99618 9 9618 9 Ethanol 95% 3888 93888 9 3888 9 SiO2 (0.15-0.2 mm) 375 9 ; SiO2 (0.25-0.3 mm) 375 9 SiO2 (0.4-0.5 mm) 375 9 400 9 of the granules according to Examples 4-6 were coated with a composition comprising Polymeric layer granulate according to Example Ethyl cellulose 10 cps 187.2 9144.0 9 92.2 9 Hydroxypropylmethyl cellulose46.8 936.0 9 23.0 9 Acetyltributylcitrate 26.0 g20.0 9 12.8 9 Methylene chloride 4428 93408 9 2168 9 Isopropylic alcohol 1114 9 858 9 546 9 The preparations were formulated as described above. In the enclosed Table 1 the release of metoprolol succinate during 20 hours is given.
; All preparations gave a controlled release of drug during a long period of time.
Example 7 Cores Magnesium chloride, hexahydrate 1100 g Ethanol 99.5% 6200 9 Silicon dioxide (0.15-0.30 mm)400 9 - l7 ~
:' .
.. .
Z5~3 Polymerlc layer Ethyl cellulose 50 cps 533 9 Methylene chloride 14107 9 Isopropylic alcohol 5481 9 Magnesium chloride ~MgC12) was sprayed onto the cores of silicon dioxide from a solution of ethanol 99.5%. 400 9 of the beads so formed were coated with ethyl cellulose 50 cps from a solution of methylene chloride and isopropylic alcohol to give granules containing 34? mg/g~magnesium chloride (MgC12). The in vitro release of drug (magnesium chloride) was 38% after 1 hour, 58~ after 2 hours and 82 after 6 hours.
Example 8 Cores --.
Ampicillin - Na 600 9 Ethanol 95% 894 9 ~` 20 Water purified 1020 9 Glass (0.5 mm) 500 9 Polymeric layer ~, Ethyl cellulose 100 cps 15 9 Methylene chloride 600 9 Isopropylic alcohol 150 9 Ampicillin-Na was sprayed onto the cores of glass from the ethanol/water solution. 500 9 of the ampicillin-Na beads were then coated with a poly-meric solution of ethyl cellulose 100 cps in methylene chloride/isopro-pylic alcohol. After 40 minutes in vitro dissolution 50% of the drug content was released from the beads.
- 1~
3~f~
Example 9 Cores . 5 Metoprolol succinate 1440 9 Methylene chloride 9618 9 Ethanol 95% 3888 9 SiO2 (0.15-0.25 mm) 375 9 ~ lO Polymeric layer : Ethyl cellulose N-lO 166.2 9 Hydroxypropylmethyl cellulose39.0 g Acetyltributylcitrate 22.8 9 Methylene chloride 3889 9 Tsopropylic alcohol 978 9 Tablet additives Microcrystalline cellulose429.3 9 ' Corn starch 67.1 9 Lactose powder 40-3 9 Polyvidone 55.5 9 ~ Water purified 314.7 9 : 25 Magnesium stearate 1.2 9 Tablet coating ~12.500 tablets) Hydroxypropylmethyl cellulose 6 cps 159.6 9 Polyethylene glycol 6000 39.9 9 Colour Titanium Dioxide 39.9 9 Water purified 1356 9 Paraffin 1 . 6 9 : ~`
Metoprolol succinate was sprayed onto the cores of silicon dioxide according to the process described in the previous examples. 400 9 of the so obtained beads (~raction 0.4-0.63 mm) were coated with the poly-:~
meric solution described aboveO The coated beads of metoprolol succinate were mixed with the additives in equal portions and after addition of Mg-stearate 0.1%, the dry mixture was compressed to tablets. Finally, the tablets were coated :Ln a coating pan with the polymeric solution described above.
The very small particles, 0.15-0.25 mm, of dense SiO2 used as the core material, contribute to a high content of drug in the small beads formed (O.4-0.63 mm) and thus to a reduced size of the final preparation.
Example 10 Metoprolol succinate 1440 g Methylene chloride 9618 g Ethanol 95% 3888 g SiO2 (0.15-0.25 mm) 375 g Polymeric layer -Ethyl cellulose 50 cps 168.1 g Hydroxypropylmethyl cellulose36.9 g Acetyltributylcitrate 22.8 g Methylene chloride 4167 g Isopropylic alcohol 815 g Tablet additives Microcrystalline cellulose470.3 g Maize starch 117.6 g Potato starch 10.5 g Water purified 342.2 g Magnesium stearate 1.2 g -- ~,0 --~ ~ ~93g~4~
Metoprolol succinate was sprayed onto the cores of sili-con dioxide according to the process described in Example l. 400 g of the granules so formed were coated with a polymeric film con-taining ethyl cellulose 50 cps, hydroxypropylmethyl cel]ulose and acetyltributylcitrate. An additional tablet mass was maae by wet granulation of the dry mixture of microcrystalline cellulose and maize starch with the potato starch-water solution in a planetary mixer. Equal amounts (600 g) of the active and additional granules were finally mixed with Mg-stearate 0.1~ and compressed to tablets.
Example 11 This example illustrates an embodiment of the invention in which the core is composed only of a salt of metoprolol; no insoluble core is present. Metoprolol succinate lO0~ in the form of compact spherical granules and having an average particle size of 0.42 mm.
400 g of the metoprolol succinate granules above of particles less than 0.63 mm were coated with Ethyl cellulose lO cps177.1 g ~ydroxypropylmethyl cellulose 38.9 g Acetyltributylcitrate 24.0 g Methylene chloride 4094 g Isopropylic alcohol 10~9 g The beads obtained were formed into pharmaceutical pre-parations as described above.
Example 12 S-enantiomeric metoprolol sorbate in the form of compact spherical granules in the fraction 0.4-0.63 mm.
~, 939L'~
40 g of the metoprolol sorbate granules above with par-ticles less than 0.63 mm together with 360 g of non-pareil granules with particles between 0.75-1.0 mm were coated with ; Ethyl cellulose 10 cps51.7 g Hydroxypropylmethyl cellulose 11.3 g Acetyltributylcitrate 7.0 g Methylene chloride 1194 g Isopropylic alcohol 300 g The beads obtained were formed into pharmaceutical pre-parations as described above.
Table 1 summarizes the drug release data for the composi-tions according to examples 1-6 and 9 and ReEerence examples 1 and .
Biopharmaceutical studies An oral application of the present invention (Example 9) is illustrated in Figure 3. The multiple-unit system was applied on metoprolol succinate in order to find a preparation for dosage once daily with an even plasma concentration profile over 24 hours.
A single dose of 190 mg metoprolol succinate (e~uivalent to 200 mg metoprolol tartrate) in a controlled release preparation according to the present invention was administered to 10 healthy male subjects. The plasma concentrations of metoprolol were com-pared with the plasma concentrations after a single dose of a sustained release tablet (Durules ~ ) based on the insoluble matrix principle containing 200 mg of metoprolol tartrate. Each point represents the mean data from the 10 subjects. As can be seen the 3 3 f~ L~
preparation according to the invention gave an almost constant plasma concentration profile of metoprolol, whereas the matrix tablet gave an unwanted high peak in the plasma concentration dur-ing the first hours after the administration.
Reduction of exercise heart rate 12 subjects were given an ordinary tablet containing lOO
mg of metoprolol tartrate once a day and the reduction of the exercise heart rate on day 5 of the treatment was measured and com-pared with the reduction of the exercise heart rate on day 5 in subjects given a controlled release preparation according to Example 9 of the invention containing 95 mg metoprolol succinate (equivalent to lOO mg metoprolol ta~trate). The reduction of the heart rate i5 illustrated in ~igure 5. As can be seen, the pre-paration according to the invention gives an even pharmacodynamic effect for 24 hours.
The best mode of carrying out the invention is at present considered to be Example 9.
- 23 _ . .
34~
o O , o~ N O C~
0~ ~ $ 0~_ O d' C~) eJ N
OD ~ C~'l 1` 0 . 00 ~' s I~
E cn ~ I o~ J N N C~
0~ ~ ~ C~
~D ~
O ~ r) ~ O ~ C~l a) ~- 11~ U~ ~D ~ 1~ ~ d- et LO
a~ 0~ cn ~ ~ co ~ ~ o~ ~ ~
5: ~
~ ~ E c ~D Ln oo ~ ~ ~ ~ a7 N ~
~) O ~ ~- 1~ ~ 1~ 0 0~ CO ~`
O O C--N C~
V ~I c~~ ~ N ~ ) ~) ~, Oa~ ,_ N
O ~ -- ~ ~ c~ Ln CO
o , o o ~ E a~
c o (~ ~, o ) oo ~ ~ ~ o V) t~
t:L ~ a~ c~l N v ~- N N C~
~ c ~ O O ~ ~ ~ O O O O
c~ O ~ n cn Z X V~
~ ~?
~ ..
S ~
~ ~- .
:: E ~ , o ,,_ ~ c~
E o _ N
- 2~ -" ' ' '" ' ' .
.
, `` ~25~3~
Table 2 and Figure 4 illustrate the in vitro release of metoprolol from the compositions according to Examples 1, 9, 10, 11 and 12. As can be seen from the table at least 50% of the dose of metoprolol is released at a rate varying between 3-7 w/w ~/hour.
~93~9 o ~ ~o ~o o CO
~ CO CO CO CO CO
CO CO CO ~ ~ ~
~o ~ I_ CO CO ~_ ~o ~ o i- o 5~ ,1 r~ O CO
O ~r cn cn co o E; ~ ~o ~o ~D ~O
~ ~a) ~ ~ ~ ~ ~ 1~
O ~ ~O ~O In ~ ~O
~o ~ o ~ ~
~ ~ ~ u~LO o ~r I
~ ~ a) n ~
a) a~
r-l ~1 h O ~ co a~ r~ o r ~`
O ~ ~ ~
a) ~ ) cn 1~ 1 $ ~ 5~ ~o ~
~ ~ P~ ~r ~1 ~ cn t~ ,1 ~o ~ U~ CO
rl H ~1 ~1 ,-1 ~) H
O O ~ ~
rl U~
O ~ ~1 '~ ~
~ & ~
~ :~ o .~ ~
~ ~ ~ ~l~ ~ ~ ~
,J o ~1 r' ~~q ~ ,1~Q U~
a~ Ql Q Q
::~ a) s-l n~
C~ ~ ~ ~
:' ~ Z ,~ CT~ ,O~
E~ ~
.
, . . .
.:. ,: . .
~ ~ E c ~D Ln oo ~ ~ ~ ~ a7 N ~
~) O ~ ~- 1~ ~ 1~ 0 0~ CO ~`
O O C--N C~
V ~I c~~ ~ N ~ ) ~) ~, Oa~ ,_ N
O ~ -- ~ ~ c~ Ln CO
o , o o ~ E a~
c o (~ ~, o ) oo ~ ~ ~ o V) t~
t:L ~ a~ c~l N v ~- N N C~
~ c ~ O O ~ ~ ~ O O O O
c~ O ~ n cn Z X V~
~ ~?
~ ..
S ~
~ ~- .
:: E ~ , o ,,_ ~ c~
E o _ N
- 2~ -" ' ' '" ' ' .
.
, `` ~25~3~
Table 2 and Figure 4 illustrate the in vitro release of metoprolol from the compositions according to Examples 1, 9, 10, 11 and 12. As can be seen from the table at least 50% of the dose of metoprolol is released at a rate varying between 3-7 w/w ~/hour.
~93~9 o ~ ~o ~o o CO
~ CO CO CO CO CO
CO CO CO ~ ~ ~
~o ~ I_ CO CO ~_ ~o ~ o i- o 5~ ,1 r~ O CO
O ~r cn cn co o E; ~ ~o ~o ~D ~O
~ ~a) ~ ~ ~ ~ ~ 1~
O ~ ~O ~O In ~ ~O
~o ~ o ~ ~
~ ~ ~ u~LO o ~r I
~ ~ a) n ~
a) a~
r-l ~1 h O ~ co a~ r~ o r ~`
O ~ ~ ~
a) ~ ) cn 1~ 1 $ ~ 5~ ~o ~
~ ~ P~ ~r ~1 ~ cn t~ ,1 ~o ~ U~ CO
rl H ~1 ~1 ,-1 ~) H
O O ~ ~
rl U~
O ~ ~1 '~ ~
~ & ~
~ :~ o .~ ~
~ ~ ~ ~l~ ~ ~ ~
,J o ~1 r' ~~q ~ ,1~Q U~
a~ Ql Q Q
::~ a) s-l n~
C~ ~ ~ ~
:' ~ Z ,~ CT~ ,O~
E~ ~
.
, . . .
.:. ,: . .
Claims (57)
1. Controlled release beads coated with a membrane control-ling drug release characterized in that they contain one or more pharmaceutically active compounds applied on a compact insoluble core material, whereby the active compound forms a compact layer on the insoluble core and this compact layer is further covered with a release controlling polymeric membrane.
2. Beads according to claim 1 characterized in that the size of the particles of the core material is 0.1-2 mm and the size of the core covered with pharmaceutically active compound is 0.2-3.0 mm.
3. Beads according to claim 2 characterized in that the core material has a size of 0.1-0.5 mm and that said core material covered with pharmaceutically active compound has a size of 0.3-1.0 mm.
4. Beads according to claim 1 characterized in that the core material is silicon dioxide.
5. Beads according to claim 1 characterized in that the core material is small particles of glass.
6. Beads according to claim 1 characterized in that they contain a pharmaceutically active compound for which a non instant drug release is wanted.
7. Beads according to claim 1 characterized in that the pharmaceutically active compound is to be administered orally or parenterally.
8. Beads according to claim 1 characterized in that the pharmaceutically active compound is used in the cardiovascular gastrointestinal or chemotherapeutic field.
9. Beads according to claim 1 characterized in that the pharmaceutically active compound is a salt of an adrenergic beta-blocking agent.
10. Beads according to claim 1 characterized in that the pharmaceutically active compound is an antibiotic.
11. Process for the preparation of beads for the production of controlled release products characterized in that a pharma-ceutically active compound dissolved in a solvent is applied onto insoluble core material with a size of 0.1-2 mm, the solvent is dried off and beads covered with a compact layer of active compound and having a size of 0.2-3.0 mm are obtained, whereafter the ob-tained beads are further covered with a release controlling poly-meric membrane.
12. Process according to claim 11 characterized in that the core material has a size of 0.1-0.5 mm and that said core material covered with pharmaceutically active compound has a size of 0.3-1.0 mm.
13. Process according to claim 11 characterized in that the core material is silicon dioxide.
14. Process according to claim 11 characterized in that the core material is small particles of glass.
15. Process according to claim 11 characterized in that the beads obtained by the process contain a pharmaceutically active compound for which a non instant drug release is wanted.
16. Process according to claim 11 characterized in that the pharmaceutically active compound is to be administered orally or parenterally.
17. Process according to claim 11 characterized in that the pharmaceutically active compound is used in the cardiovascular, gastrointestinal or chemotherapeutic field.
18. Process according to claim 11 characterized in that the pharmaceutically active compound is a salt of an adrenergic beta-blocking agent.
19. Process according to claim 11 characterized in that the pharmaceutically active compound is an antibiotic.
20. Use of beads according to any one of claim 1 to claim 10 to control release of a therapeutically active compound in a host.
21. Controlled release preparation containing a salt of metoprolol characterized in that the preparation contains a number of beads comprising a salt of metoprolol as the main soluble com-ponent and that said beads are coated with a polymeric membrane containing derivatives of cellulose without protolysable groups and whereby at least 75% of the dose of metoprolol is released with-in 20 hours virtually independent of the pH in the interval 1-8.
22. Preparation according to claim 21 characterized in that the size of the beads is in the range of 0.25-2 mm.
23. Preparation according to claim 21 characterized in that the size of the beads is in the range of 0.35-1.0 mm.
24. Preparation according to claim 21 characterized in that at least 50% of the dose of metoprolol is released at the rate 3-7 w/w %/hour.
25. Preparation according to claim 21 characterized in that the salt of metoprolol has a solubility less than 600 mg/ml in water at 25°C, preferably 30-600 mg/ml.
26. Preparation according to claim 25 characterized in that the salt is formed of an organic carboxylic acid.
27. Preparation according to claim 26 characterized in that the salt of metoprolol is the succinate or fumarate of racemic metoprolol.
28. Preparation according to claim 26 characterized in that the salt of metoprolol is the benzoate or sorbate of the S-enantiomer of metoprolol.
29. Preparation according to claim 1 characterized in that the uncoated beads comprise at least 95 w/w % of metoprolol.
30. Preparation according to claim 21 characterized in that the uncoated beads comprise a salt of metoprolol applied on an insoluble core.
31. Preparation according to claim 30 characterized in that the insoluble cores have a size of 0.1-1.0 mm, preferably 0.15-0.3 mm.
32. Preparation according to claim 30 characterized in that the insoluble cores have a size of 0.15-0.3 mm and are covered by a salt of metoprolol to give beads having a size of 0.35-1.0 mm which are coated with the polymeric membrane.
33. Preparation according to claim 29 characterized in that the uncoated beads having a size of 0.35-1.0 mm comprise a salt of metoprolol as such and are coated with the polymeric membrane.
34. Preparation according to claim 21 characterized in that the polymeric membrane contains ethyl cellulose.
35. Preparation according to claim 21 characterized in that the polymeric membrane contains ethyl cellulose together with hydroxypropylmethyl cellulose.
36. A pharmaceutical preparation containing the controlled release preparation according to claim 21 characterized in that the coated beads are filled into hard gelatine capsules.
37. A pharmaceutical preparation containing the controlled release preparation according to claim 21 characterized in that the coated beads together with pharmaceutical additives are com-pressed to tablets which disintegrate into the primary formed coated beads when the tablets are brought into contact with gastro-intestinal fluids.
38. Process for the preparation of a controlled release pre-paration containing a salt of metoprolol characterized in that a number of beads comprising a salt of metoprolol as the main soluble component are spray coated with a membrane-forming solution giving a polymeric membrane containing derivatives of cellulose without protolysable groups whereby a preparation is obtained which re-leases at least 75% of the dose of metoprolol within 20 hours virtually independent of the pH in the interval 1-8.
39. Process according to claim 38 characterized in that the size of the beads is in the range of 0.25-2 mm.
40. Process according to claim 39 characterized in that the size of the beads is in the range of 0.35-1.0 mm.
41. Process according to claim 38 characterized in that at least 50% of the dose of metoprolol is released at the rate 3-7 w/w %/hour.
42. Process according to claim 38 characterized in that the salt of metoprolol has a solubility less than 600 mg/ml in water at 25°C.
43. Process according to claim 38 characterized in that the salt of metoprolol has a solubility of 30-600 mg/ml in water at 25°C.
44. Process according to claim 42 characterized in that the salt is formed of an organic carboxylic acid.
45. Process according to claim 44 characterized in that the salt of metoprolol is the succinate or fumarate of racemic meto-prolol.
46. Process according to claim 44 characterized in that the salt of metoprolol is the benzoate or sorbate of the S-enantiomer of metoprolol.
47. Process according to claim 38 characterized in that the uncoated beads comprise at least 95 w/w % of metoprolol.
48. Process according to claim 38 characterized in that the uncoated beads comprise a salt of metoprolol applied on an in-soluble core.
49. Process according to claim 48 characterized in that the insoluble cores have a size of 0.1-1.0 mm, preferably 0.15-0.3 mm.
50. Process according to claim 48 characterized in that the insoluble cores have a size of 0.15-0.3 mm and are covered by a salt of metoprolol to give beads having a size of 0.35-1.0 mm which are coated with the polymeric membrane.
51. Process according to claim 47 characterized in that the uncoated beads having a size of 0.35-1.0 mm comprise a salt of metoprolol as such and are coated with the polymeric membrane.
52. Process according to claim 38 characterized in that the polymeric membrane contains ethyl cellulose.
53. Process according to claim 38 characterized in that the polymeric membrane contains ethyl cellulose together with hydroxy-propylmethyl cellulose.
54. A process for the manufacture of a pharmaceutical prepara-tion containing the controlled release preparation according to claim 38 characterized in that the coated beads are filled into hard gelatine capsules.
55. A process for the manufacture of a pharmaceutical prepara-tion containing the controlled release preparation according to claim 38 characterized in that the coated beads together with pharmaceutical additives are compressed to tablets which disinte-grate into the primary formed coated beads when the tablets are brought into contact with gastrointestinal fluids.
56. Method of producing a preparation according to claim 21 characterized in that beads comprising a salt of metoprolol as the main soluble component are spray coated with a membrane-forming solution containing derivatives of cellulose.
57, Use of a-therapeutically effective amount of a preparation according to any one of claim 21 to claim 37 to treat a cardiovascular disorder in a mammal.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE8504720-7 | 1985-10-11 | ||
| SE8504721A SE455836B (en) | 1985-10-11 | 1985-10-11 | PREPARATION WITH CONTROLLED RELEASE CONTAINING A SALT OF METOPROLOL AND METHOD FOR PREPARING THIS PREPARATION |
| SE8504720A SE450087B (en) | 1985-10-11 | 1985-10-11 | GRAINS WITH CONTROLLED RELEASE OF PHARMACIFICALLY ACTIVE SUBSTANCES APPLIED SIGNED ON A COMPACT INSULABLE NUCLEAR MATERIAL |
| SE8504721-5 | 1985-10-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1293449C true CA1293449C (en) | 1991-12-24 |
Family
ID=26659105
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000520266A Expired - Lifetime CA1293449C (en) | 1985-10-11 | 1986-10-10 | Controlled release drug preparation |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1293449C (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2120881A2 (en) * | 2007-02-23 | 2009-11-25 | Glatt Air Techniques, Inc. | Method of determining the weight of the coating to be applied to form a controlled release dosage form |
-
1986
- 1986-10-10 CA CA000520266A patent/CA1293449C/en not_active Expired - Lifetime
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2120881A2 (en) * | 2007-02-23 | 2009-11-25 | Glatt Air Techniques, Inc. | Method of determining the weight of the coating to be applied to form a controlled release dosage form |
| EP2120881A4 (en) * | 2007-02-23 | 2012-11-07 | Glatt Air Tech Inc | Method of determining the weight of the coating to be applied to form a controlled release dosage form |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU593038B2 (en) | New drug preparation with controlled release of the active compound, a method for the manufacture thereof and the use of the new preparation | |
| US5246714A (en) | Drug preparation | |
| EP0220143B1 (en) | New pharmaceutical preparation with controlled release of metoprolol, a method for the manufacture thereof and the use of the new preparation | |
| RU2136283C1 (en) | Preparation of controlled drug release and method of its preparing, method of treatment | |
| US4904476A (en) | Formulations providing three distinct releases | |
| US5952005A (en) | Controlled release preparation for administering morphine | |
| US4728512A (en) | Formulations providing three distinct releases | |
| CA2140254C (en) | Controlled release morphine preparation | |
| US4794001A (en) | Formulations providing three distinct releases | |
| KR20020031338A (en) | Morphine sulphate microgranules, method for preparing same and compositions containing same | |
| CA1293449C (en) | Controlled release drug preparation | |
| HRP920590A2 (en) | New pharmaceutical preparation | |
| SI8710339A8 (en) | Process for obtaining pharmaceutical composition of metoprolol with controlled release | |
| HRP920593A2 (en) | New drug preparation |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |