CA1297025C - Controlled release hydromorphone composition - Google Patents
Controlled release hydromorphone compositionInfo
- Publication number
- CA1297025C CA1297025C CA000550717A CA550717A CA1297025C CA 1297025 C CA1297025 C CA 1297025C CA 000550717 A CA000550717 A CA 000550717A CA 550717 A CA550717 A CA 550717A CA 1297025 C CA1297025 C CA 1297025C
- Authority
- CA
- Canada
- Prior art keywords
- dosage form
- hydromorphone
- weight
- hours
- alcohol
- 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
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- 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
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
Abstract
ABSTRACT
A solid controlled release, oral dosage form, the dosage form comprising a therapeutically effective amount of hydromorphone or a salt thereof in a matrix wherein the dissolution rate in vitro of the dosage form, when measured by the USP Paddle Method at 100rpm in 900ml aqueous buffer (pH between 1.6 and 7.2) at 37°C is between 12.5% and 42.5% (by weight) hydromorphone released after l hour, between 25% and 55% (by weight hydromorphone released after 2 hours, between 45% and 75% (by weight) hydromorphone released after 4 hours and between 55% and 85% by weight) hydromorphone released after 6 hours, the in vitro release rate being independent of pH
between pH 1.6 and 7.2 and chosen such that the peak plasma level of hydromorphone obtained in vivo occurs between 2 and 4 hours after administration of the dosage form.
A solid controlled release, oral dosage form, the dosage form comprising a therapeutically effective amount of hydromorphone or a salt thereof in a matrix wherein the dissolution rate in vitro of the dosage form, when measured by the USP Paddle Method at 100rpm in 900ml aqueous buffer (pH between 1.6 and 7.2) at 37°C is between 12.5% and 42.5% (by weight) hydromorphone released after l hour, between 25% and 55% (by weight hydromorphone released after 2 hours, between 45% and 75% (by weight) hydromorphone released after 4 hours and between 55% and 85% by weight) hydromorphone released after 6 hours, the in vitro release rate being independent of pH
between pH 1.6 and 7.2 and chosen such that the peak plasma level of hydromorphone obtained in vivo occurs between 2 and 4 hours after administration of the dosage form.
Description
CONTROLLEG RELEASE HYDROMORPHONE COMPOSITION
.
The present invention relates to a solid, controlled release, oral dosage form containing hydromorphone for use in the treatment of moderate to severe pain.
According to the present invention there is provided a solid, controlled release, oral dosage form, the dosage form comprising a therapeutically effective amount of hydromorphone or a salt thereof in a matrix wherein the dissolution rate ln vitro of the dosage form, when measured by the USP Pad~le Method at 100 rpm in 900 ml, aqueous buffer (pH between 1,6 and 7.2) at 37C is between 12.5 and 42.5X (by wt~
hydromorphone released after I hour, between 25 and 55g (by wt) hydromorphone released after 2 hours, between 45 and 75 (by wt9 hydromorphone released after 4 hours and between 55 and 85~ (by wt) hydromorphone released after 6 hours, the ln vitro release rate being independent of pH between pH 1.6 and 7.2 and such that the peak plasma level of hydromorphone obtained in vivo occurs between 2 and 4 hours after administra~ion of the dosage form.
Preferably, the dosage form contains an analgesically effective amount of hydromorphone or a salt thereof.
USP Paddle Mbthod is the Paddle Method described in US
Pharmacopoeia XXI (19851.
In the present specification, "independent of pH" means that the difference, at any given time, between the amount of hydro~orphone released at pH 1.6 and the amount released at any other pH up to, and including, pH 7.2 (when measured in vitro using the USP Paddle Method at 100rpm in 900ml aqueous buffer) is 10X (by weight) or less. The amounts released being, in all cases. a mean of at least three experiments.
'~
. .
, .
.
The present invention relates to a solid, controlled release, oral dosage form containing hydromorphone for use in the treatment of moderate to severe pain.
According to the present invention there is provided a solid, controlled release, oral dosage form, the dosage form comprising a therapeutically effective amount of hydromorphone or a salt thereof in a matrix wherein the dissolution rate ln vitro of the dosage form, when measured by the USP Pad~le Method at 100 rpm in 900 ml, aqueous buffer (pH between 1,6 and 7.2) at 37C is between 12.5 and 42.5X (by wt~
hydromorphone released after I hour, between 25 and 55g (by wt) hydromorphone released after 2 hours, between 45 and 75 (by wt9 hydromorphone released after 4 hours and between 55 and 85~ (by wt) hydromorphone released after 6 hours, the ln vitro release rate being independent of pH between pH 1.6 and 7.2 and such that the peak plasma level of hydromorphone obtained in vivo occurs between 2 and 4 hours after administra~ion of the dosage form.
Preferably, the dosage form contains an analgesically effective amount of hydromorphone or a salt thereof.
USP Paddle Mbthod is the Paddle Method described in US
Pharmacopoeia XXI (19851.
In the present specification, "independent of pH" means that the difference, at any given time, between the amount of hydro~orphone released at pH 1.6 and the amount released at any other pH up to, and including, pH 7.2 (when measured in vitro using the USP Paddle Method at 100rpm in 900ml aqueous buffer) is 10X (by weight) or less. The amounts released being, in all cases. a mean of at least three experiments.
'~
. .
, .
2 ~2~
In the present specification, "peak plasma level of hydromorphone obtained in vivo" refers to the maximum mean concentration of hydromorphone found in the plasma of at least six healthy volunteers, when (the volunteers are) subjected to a single dose, pharmacokinetic study.
Preferably the dissolution rate is between 17.5 and 37.5~ (by wt) hydromorphone released after 1 hour, between 30 and 50 (by wt) after 2 hours, between 50 and 70X (by wt) after 4 hours and between 60 and 80~ (by wt) after 6 hours.
Most preferably, the dissolution rate is between 22.5 and 32.5X (by wt) hydromorphone released after 1 hour, between 35 and 45% (by wt) after 2 hours, between 55 and 65X (by wt) after 4 hours and between 65 and 75~ (by wt) after 6 hours.
Preferably the peak plasma level of hydromorphone is obtained in vivo between 2.25 and 3.75 hours after administration of -the dosage form.
When the hydromorphone is administered as hydromorphone hydrochloride and the method of hydromorphone in plasma analysis is a double antibody radioimmunoassay (as hereinafter described), the peak plasma level of hydromorphone (per ml. of plasma) is preferably between 0.5 x 10-6 and 2.0 x 10-6, most preferably between 0.5 x 10-6 and 1.5 x 10-6, of the amount of hydromorphone hydrochloride adminis~ered orally.
Thus, if 4mg of hydromorphone hydrochloride is administered, the peak plasma level of hydromorphone is preferably between 2 and 8ngml~l, especially between 2 and 6ngml~1.
When hydromorphone base or a salt other than the hydrochloride is administered, the preferred ra~io of drug .
' . . . ' . ' ' .
administered to peak plasl~ level of hydromorphone must be adjusted according to the molecular weight of the base or salt By keeping within these narrow ranges for in vitro dissolution rates, the present inventors have surprisingly found that although the present oral dosage forms give peak plasma levels of hydromorphone between 2 and 4 hours after administration, they still afford therapeutic levels o-f hydromorphone in ViYo over at least a 12 hour period, and may therefore be used on a twice daily basis.
In order to obtain a controlled release drug dosage form having at least a 12 hour therapeutic effect, it is usual in the pharmaceutical art to produce a formulation that gives a peak plasma level of the drug between about 4-8 hours after administration (in a single dose study). The present inventors have surprisingly found that, in the case of hydromorphone, a peak plasma level at between 2-4 hours af~er administration gives at least 12 hours pain relief and, most surprisingly, that the pain relief obtained with such a formulation is greater than that achieved with formulations giving peak plasma levels (of hydromorphone) in the normal period of 1-2 hours after administration.
.
Furthermore, in the case of the present dosage form, therapeutic levels are generally achieved without concurrent side effects, such as nausea, vomitiny, constipation and drowsiness, which are often associated with high blood levels of hydromorphone. There is also evidence to suggest that the use of ~he present dosage forms leads to a reduced risk of drug addiction.
A further advantage of the present composition, which releases - --- ~ .
:' ' ~ ' . . ,' ~ ' . .. , : . .
.: - . , . .
hydromorphone at d rate that is independent of pH between 1.6 and 7.2, is that it avoids dose dumping upon oral administration. In other words, the hydromorphone is reledsed evenly throughout the gastrointestinal tract.
The present oral dosage form may be presented as, for example, granules, spheroids or pellets in a capsule or in any other suitable solid form. Preferably, however, the oral dosage form is a tablet.
The present oral dosage form preferably contains be~ween 1 and 100 mg, especially between 2 and 50 mg, most especially between 2 and 40mg, of hydromorphone hydrochloride.
Alternatively the dosage form may contain molar equivalent amounts of other hydromorphone salts or of the hydromorphone base.
The present matrix may be any matrix that affords in vitro dissolution rates of hydromorphone within the narrow ranges required and that releases the hydromorphone in a pH
independent manner, Preferably the matrix is a controlled release matrix, although normal release matrices having a coating that controls the release of the drug ~ay be used.
Suitable materials for inclusion in a controlled release matrix are (a) Hydrophilic or hydrophobic polymers, such as gums, cellulose ethers, acrylic resins and protein derived m~terials. Of these polymers, the cellulose ethers, especially hydroxyalkylcelluloses and carboxyalkylcelluloses9 are preferred, The oral dosage form may contain betwee~ 1X and 80~ (by weight) of at least one hydrophilic or hydrophobic polymer.
5 ~ 7(Ji;~
(b) Digestible, long chain (Cg-Cso, expecially ~12-C40)~
substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral and vegetable oils and waxes. HYdrocarbons having a melting point of between 25 and 90C are preferred. Of these long chain hydrocarbon materials, fatty (aliphatic) alcohols are preferred. The oral dosage form may contain up to 60%
(by weight) of at least one digestible, long chain hydrocarbon.
(c) Polyalkylene glycols. The oral dosage form may contain up to 60~ (by weight) of at least one polyalkylene ~lycol.
One particularly suitable matrix comprises at least one water soluble hydroxyalkyl cellulose, at least one C12 C36, preferably C14-C22, aliphatic alcohol and, optionally, a~
least one polyalkylene glycol.
The at least one hydroxyalkyl cellulose is preferably a hydroxy (C1 to C6) alkyl cellulose, such as hydroxypropylcellulose, hydroxypropylmethylcellulose and, especially, hydroxyethyl cellulose. The amount of the at least one hydroxyalkyl cellulose in the present oral dosage form will be determined, inter alia, by the precise rate of hydromorphone release required. Pref~rably however, the oral dosage form contains between 5% and 25X, especially between 6.25~ and 15X (by wt) of the at leas~ one hydroxyalkyl cellulose.
The at least one aliphatic alcohol may be, for example, lauryl alcohol, myristyl alcohol or stearyl alcohol. In particularly preferred embodiments of the present oral dosage form, however, the at least one aliphatic alcohol is cetyl alcohol or cetostearyl alcohol. The amount of the at least one .
:
6 ~ 37~
aliphatic alcohol in the present oral dosage form will be determined, as above, by the precise rate of hydromorphone release required. It will also depend on whether at least one polyalkylene glycol is present in or absent from the oral dosage form. In the absence of at least one polyalkylene glycol, the oral dosage form preferably contains between 20%
and 50~, especially between 25% and 45% (by wt) o~ the at least one alipha~ic alcohol. When at least one polyalkylene glycol is present in the oral dosage Form, then the combined weight of the at least one aliphatic alcohol and the atleast one polyalkylene glycol preferably constitutes between 20Z
and 50%, especially between 25~ and 45X (by wt) of th~ total dosage form.
In the present preferred dosage form, the ratio of the at least one hydroxyalkyl cellulose to the at least one aliphatic alcohol/polyalkylene glycol determines, to a considerable extent, the release ra~e of the hydromorphone from the formulation. A ratio of the at least one hydroxyalkyl cellulose to the at least one aliphatic alcohol/polyalkylene glycol of between 1:2 and 1:4 is preferred, with a ratio of between 1:3 and 1:4 being particularly preferred.
The at least one polyalkylene glycol may be, for example, polypropylene glycol or, which is preferred, polyethylene glycol. The number average molecular weight of the at least one polyalkylene glycol is preferred between 1000 and 15000 especially between 1500 and 12000.
Another suitable controlled release matrix would comprise an alkylcellulose (especially ethyl cellulose), a C12 to C36 aliphatic alcohol and, optionally, a polyalkylene glycol.
In addition to the above ingredients, a controlled release 7 ~ 76~`Z5 matrix may also contain suitable quantities of other materials, e.g. diluents, lubricants, binders, granulating aids, colorants, flavorants and glidants that are conventional in the pharmaceutical art.
As an alternative to a controlled release matrix, the presenk matrix may be a normal release matrix having a coat that controls the release of the drug. In a particularly pre~erred embodiment of this aspect of the invention, the present dosage form comprises film coated spheroids containing active ingredient and a non-water soluble spheronising agent. The term spheroid is known in the pharmaceutical art and means a spherical granule having a diameter of between 0.5mm and 2.5mm, especially between O.Smm and 2mm.
The spheronising agent may be any pharmaceutically acceptable material that, together with the active ingredient, can be spheronised to form spheroids. Microcrystalline cellulose is preferred.
A suitable microcrystalline cellulose is, for e~ample, the material sold as Avicel PH 101 (Trade Mark, FMC Corporation).
According to a preferred aspect of the present invention, the film coated spheroids contain between 70~ and 9~g (~y wt), especially be~ween 80% and 95g (by w~), of ~he spheronising agent, especially microcrystalline cellulose.
In addition to the active ingredient and spheronising agent, the spheroids may also contain a binder. Suitable binders, such as low vîscosity, water soluble polymers, will be well known ~o those skilled in the pharmaceutical art. However, wa~er soluble hydroxy lower alkyl celluloses, such as hydroxy propyl cellulose, are pre~erred. Additionally (or alternatively) the spheroids may contain a water insoluble polymer, especially an acrylic polymer, an acrylic copolymer, such as a methacrylic acid-ethyl acrylate copolymer, or ethyl cellulose.
The spheroids are film coated with a material that permits release of the hydromorphone (or salt) at a contro11ed rate in an aqueous medium. The film coat is chosen so as to achieve, in combination with the spheroids' other ingredients, the in-vitro re1ease rate outlined above (between 12.5% and 42.5%
(by wt) release after 1 hour, etc.).
The film coat will generally include a water insoluble material such as (a) a wax, either alone or in admixture with a fat~y alcohol, (b) shellac or zein, (c~ a water insoluble cellulose, especially ethyl cellulose, (d) a polymethacrylate, especially Eudragit (Trade Mark).
Preferably, the film coat comprises a mixture of the water insoluble material and a water soluble material. The ratio of water insoluble to water soluble material is de~ermined by, amongst other factors, the release rate required and the solubility charac~eris~ics of the materials selected.
The water soluble material may be, for example, polyvinylpyrrolidone or, which is preferred, a water soluble cellulose, especially h~droxypropylmethyl cellulose.
Suitable combinations of water insoluble and water soluble materials for the film coat include shellac and . ~ . . . .
~ .
9 ~ ?d~3 7~G ~ ~
polyvinylpyrrolidone or, which is preferred, ethyl cellulose and hydroxypropylmethyl cellulose.
In order to facilitate the preparation of a solid, controlled release, oral dosage form according to this invention there is provided, in d further aspect of the present invention, a process for the preparation of a solid, controlled release, oral dosage form according to the present invention comprising incorporating hydromorphone or a salt thereof in a controlled re1ease matrix. Incorporation in the matrix may be effected, for example, by (a) forming granules comprising at least one water soluble hydroxyalkyl cellulose and hydromorphone or a hydromorphone salt, (b) mixing the hydroxyalkyl cellulose containing granules with at least one CI2-C3b aliphatic alcohol, and (c) optionally, compressing and shaping the granules, Preferably, the granules are formed by wet granulating the hydroxyalkyl cellulose/hydromorphone with water. In a particularly preferred embodiment of this process, the amount of water added during the wet granulation step is preferably between 1.5 and 5 times, especially be~ween 1.75 and 3.5 ~imes, the dry weight of the hydroxyalkylcellulose.
The present solid, controlled release, oral dosage form may also be prepared, in the form of film coated spheroids, by (a) blending a mixture comprising hydromorphone or a hydromorphone salt and a non-water soluble spheronising agent, ~25~ ,S
(b) extruding the blended mixture to give an extrudate, (c) spheronising the extrudate until spheroids are formed, and (d) coating the spheroids with a film coat.
Tne present solid, controlled release, oral dosage form and processes for its preparation w;ll now be described by way of example only.
Exampl_ Hydromorphone hydrochloride (4.0gm) was wet granulated with lactose monohydrate (167.0gm) and hYdroxYethYl cellulose ~40.0gm; Natrosol 250 ~X, Trade Mark) and the granules were sieved through a 12 mesh screen. The granules were then dried in a Fluid Bed Dryer at 50C and passed through a 16 mesh screen.
To the warmed hydromorphone containing granules was added molten cetostearyl alcohol (120.0gm) and the whole was mixed thoroughly. ~he mixture was allowed to cool in the air, regranulated and sieved through a 16 mesh screen.
Purified Talc ~6.0gm) and magnesium stearate (3.0gm) were then added and mixed with ~he granules. The granules were then compressed into 1000 tablets each containing, mg/tablet Hydromorphone Hydrochloride 4.0 Lactose Monohydrate 167.0 Hydrox~ethylcellulose 40.0 Cetostearyl alcohol 120.0 , .
. . ~ ~ ~ .. . .
.
:
~ 7 ~2 S
Purified Talc 6.0 Magne-sium stearate 3.
Example 2 The procedure of Example 1 was followed, but with reduced quantities of cellulose and fatty alcohol, to give 1000 tablets each containing, ~_~ab!et Hydromorphone Hydrochloride 4.0 Anhydrous Lactose 167.0 Hydroxyethylcellulose 30.0 Cetostearyl Alcohol ~0.0 Purified Talc ~.0 Magnesium Stearate 3.0 Example 3 Hydromorphone hydroehloride (4.09m~ was wet granulated wi~h lactose monohydrate (30.0gm) hydroxyethyl cellulose ~lO.Ogm;
Natrosol 250 HX, Trade Mark) and mæthacrylic acid copolymer (30.0gm, Eudragit L-1~0-55; Trade Mark) and the granules were sieved through a 12 mesh screen. The granules were then dried in a Fluid Be~ Dryer at 50C and passed through a 16 mesh screen.
To the warmed hydromorphone containing granules was added molten cetostearyl alcohol (30.0gm) and the whole was mixed thoroughly. The~mixture was allowed to cool in ~he air, regranulated and sieved through a 16 mesh screen.
The granules were then compressed into 1000 table~s each containing, ,;
: -~ 7 m~/tablet Hydromorphone Hydrochloride 4.0 Lactose Monohydrate 30.0 Hydroxyethylcellulose 10.0 Methacrylic Acid Copolymer 30.0 Cetostearyl alcohol 30.0 Examp_e 4 Hydromorphone hydrochloride (509) microcrystalline ce11ulose ~Avicel PH101, 440g) and hydroxypropylmethyl ce11ulose (Methocel E15, 109) were dry mixed. Water (350ml) was then added and the mixture was granulated. The granulated mass was extruded through a lmm cylinder and the extrudate was spheronised. The resultant spheroids were dried at 60C in a fluid bed drier. The moisture content of the drled spheroids was found to be 4.3~ w/w (Karl-Fischer). The dried spheroids were then sieved and the sieve fraction between 1.0mm and 1.4mm was retained.
The spheroids were co~ted with a film coat, having the formulation given below, to a level of 15~ w/w.
Film Coat Formulation Ethylcellulose N10 ~ 4.0X w/v Hydroxypropylmethylcellulose (Methocel E15) 1.0~ w/v Propylene glycol BP 0.5X w/v Opaspray K-1-4132 3.0~ w/v Methanol 60.0X v/v Dichloromethan2 to lQ0.0~ v/v Tt~le- tha~
, .
In the present specification, "peak plasma level of hydromorphone obtained in vivo" refers to the maximum mean concentration of hydromorphone found in the plasma of at least six healthy volunteers, when (the volunteers are) subjected to a single dose, pharmacokinetic study.
Preferably the dissolution rate is between 17.5 and 37.5~ (by wt) hydromorphone released after 1 hour, between 30 and 50 (by wt) after 2 hours, between 50 and 70X (by wt) after 4 hours and between 60 and 80~ (by wt) after 6 hours.
Most preferably, the dissolution rate is between 22.5 and 32.5X (by wt) hydromorphone released after 1 hour, between 35 and 45% (by wt) after 2 hours, between 55 and 65X (by wt) after 4 hours and between 65 and 75~ (by wt) after 6 hours.
Preferably the peak plasma level of hydromorphone is obtained in vivo between 2.25 and 3.75 hours after administration of -the dosage form.
When the hydromorphone is administered as hydromorphone hydrochloride and the method of hydromorphone in plasma analysis is a double antibody radioimmunoassay (as hereinafter described), the peak plasma level of hydromorphone (per ml. of plasma) is preferably between 0.5 x 10-6 and 2.0 x 10-6, most preferably between 0.5 x 10-6 and 1.5 x 10-6, of the amount of hydromorphone hydrochloride adminis~ered orally.
Thus, if 4mg of hydromorphone hydrochloride is administered, the peak plasma level of hydromorphone is preferably between 2 and 8ngml~l, especially between 2 and 6ngml~1.
When hydromorphone base or a salt other than the hydrochloride is administered, the preferred ra~io of drug .
' . . . ' . ' ' .
administered to peak plasl~ level of hydromorphone must be adjusted according to the molecular weight of the base or salt By keeping within these narrow ranges for in vitro dissolution rates, the present inventors have surprisingly found that although the present oral dosage forms give peak plasma levels of hydromorphone between 2 and 4 hours after administration, they still afford therapeutic levels o-f hydromorphone in ViYo over at least a 12 hour period, and may therefore be used on a twice daily basis.
In order to obtain a controlled release drug dosage form having at least a 12 hour therapeutic effect, it is usual in the pharmaceutical art to produce a formulation that gives a peak plasma level of the drug between about 4-8 hours after administration (in a single dose study). The present inventors have surprisingly found that, in the case of hydromorphone, a peak plasma level at between 2-4 hours af~er administration gives at least 12 hours pain relief and, most surprisingly, that the pain relief obtained with such a formulation is greater than that achieved with formulations giving peak plasma levels (of hydromorphone) in the normal period of 1-2 hours after administration.
.
Furthermore, in the case of the present dosage form, therapeutic levels are generally achieved without concurrent side effects, such as nausea, vomitiny, constipation and drowsiness, which are often associated with high blood levels of hydromorphone. There is also evidence to suggest that the use of ~he present dosage forms leads to a reduced risk of drug addiction.
A further advantage of the present composition, which releases - --- ~ .
:' ' ~ ' . . ,' ~ ' . .. , : . .
.: - . , . .
hydromorphone at d rate that is independent of pH between 1.6 and 7.2, is that it avoids dose dumping upon oral administration. In other words, the hydromorphone is reledsed evenly throughout the gastrointestinal tract.
The present oral dosage form may be presented as, for example, granules, spheroids or pellets in a capsule or in any other suitable solid form. Preferably, however, the oral dosage form is a tablet.
The present oral dosage form preferably contains be~ween 1 and 100 mg, especially between 2 and 50 mg, most especially between 2 and 40mg, of hydromorphone hydrochloride.
Alternatively the dosage form may contain molar equivalent amounts of other hydromorphone salts or of the hydromorphone base.
The present matrix may be any matrix that affords in vitro dissolution rates of hydromorphone within the narrow ranges required and that releases the hydromorphone in a pH
independent manner, Preferably the matrix is a controlled release matrix, although normal release matrices having a coating that controls the release of the drug ~ay be used.
Suitable materials for inclusion in a controlled release matrix are (a) Hydrophilic or hydrophobic polymers, such as gums, cellulose ethers, acrylic resins and protein derived m~terials. Of these polymers, the cellulose ethers, especially hydroxyalkylcelluloses and carboxyalkylcelluloses9 are preferred, The oral dosage form may contain betwee~ 1X and 80~ (by weight) of at least one hydrophilic or hydrophobic polymer.
5 ~ 7(Ji;~
(b) Digestible, long chain (Cg-Cso, expecially ~12-C40)~
substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral and vegetable oils and waxes. HYdrocarbons having a melting point of between 25 and 90C are preferred. Of these long chain hydrocarbon materials, fatty (aliphatic) alcohols are preferred. The oral dosage form may contain up to 60%
(by weight) of at least one digestible, long chain hydrocarbon.
(c) Polyalkylene glycols. The oral dosage form may contain up to 60~ (by weight) of at least one polyalkylene ~lycol.
One particularly suitable matrix comprises at least one water soluble hydroxyalkyl cellulose, at least one C12 C36, preferably C14-C22, aliphatic alcohol and, optionally, a~
least one polyalkylene glycol.
The at least one hydroxyalkyl cellulose is preferably a hydroxy (C1 to C6) alkyl cellulose, such as hydroxypropylcellulose, hydroxypropylmethylcellulose and, especially, hydroxyethyl cellulose. The amount of the at least one hydroxyalkyl cellulose in the present oral dosage form will be determined, inter alia, by the precise rate of hydromorphone release required. Pref~rably however, the oral dosage form contains between 5% and 25X, especially between 6.25~ and 15X (by wt) of the at leas~ one hydroxyalkyl cellulose.
The at least one aliphatic alcohol may be, for example, lauryl alcohol, myristyl alcohol or stearyl alcohol. In particularly preferred embodiments of the present oral dosage form, however, the at least one aliphatic alcohol is cetyl alcohol or cetostearyl alcohol. The amount of the at least one .
:
6 ~ 37~
aliphatic alcohol in the present oral dosage form will be determined, as above, by the precise rate of hydromorphone release required. It will also depend on whether at least one polyalkylene glycol is present in or absent from the oral dosage form. In the absence of at least one polyalkylene glycol, the oral dosage form preferably contains between 20%
and 50~, especially between 25% and 45% (by wt) o~ the at least one alipha~ic alcohol. When at least one polyalkylene glycol is present in the oral dosage Form, then the combined weight of the at least one aliphatic alcohol and the atleast one polyalkylene glycol preferably constitutes between 20Z
and 50%, especially between 25~ and 45X (by wt) of th~ total dosage form.
In the present preferred dosage form, the ratio of the at least one hydroxyalkyl cellulose to the at least one aliphatic alcohol/polyalkylene glycol determines, to a considerable extent, the release ra~e of the hydromorphone from the formulation. A ratio of the at least one hydroxyalkyl cellulose to the at least one aliphatic alcohol/polyalkylene glycol of between 1:2 and 1:4 is preferred, with a ratio of between 1:3 and 1:4 being particularly preferred.
The at least one polyalkylene glycol may be, for example, polypropylene glycol or, which is preferred, polyethylene glycol. The number average molecular weight of the at least one polyalkylene glycol is preferred between 1000 and 15000 especially between 1500 and 12000.
Another suitable controlled release matrix would comprise an alkylcellulose (especially ethyl cellulose), a C12 to C36 aliphatic alcohol and, optionally, a polyalkylene glycol.
In addition to the above ingredients, a controlled release 7 ~ 76~`Z5 matrix may also contain suitable quantities of other materials, e.g. diluents, lubricants, binders, granulating aids, colorants, flavorants and glidants that are conventional in the pharmaceutical art.
As an alternative to a controlled release matrix, the presenk matrix may be a normal release matrix having a coat that controls the release of the drug. In a particularly pre~erred embodiment of this aspect of the invention, the present dosage form comprises film coated spheroids containing active ingredient and a non-water soluble spheronising agent. The term spheroid is known in the pharmaceutical art and means a spherical granule having a diameter of between 0.5mm and 2.5mm, especially between O.Smm and 2mm.
The spheronising agent may be any pharmaceutically acceptable material that, together with the active ingredient, can be spheronised to form spheroids. Microcrystalline cellulose is preferred.
A suitable microcrystalline cellulose is, for e~ample, the material sold as Avicel PH 101 (Trade Mark, FMC Corporation).
According to a preferred aspect of the present invention, the film coated spheroids contain between 70~ and 9~g (~y wt), especially be~ween 80% and 95g (by w~), of ~he spheronising agent, especially microcrystalline cellulose.
In addition to the active ingredient and spheronising agent, the spheroids may also contain a binder. Suitable binders, such as low vîscosity, water soluble polymers, will be well known ~o those skilled in the pharmaceutical art. However, wa~er soluble hydroxy lower alkyl celluloses, such as hydroxy propyl cellulose, are pre~erred. Additionally (or alternatively) the spheroids may contain a water insoluble polymer, especially an acrylic polymer, an acrylic copolymer, such as a methacrylic acid-ethyl acrylate copolymer, or ethyl cellulose.
The spheroids are film coated with a material that permits release of the hydromorphone (or salt) at a contro11ed rate in an aqueous medium. The film coat is chosen so as to achieve, in combination with the spheroids' other ingredients, the in-vitro re1ease rate outlined above (between 12.5% and 42.5%
(by wt) release after 1 hour, etc.).
The film coat will generally include a water insoluble material such as (a) a wax, either alone or in admixture with a fat~y alcohol, (b) shellac or zein, (c~ a water insoluble cellulose, especially ethyl cellulose, (d) a polymethacrylate, especially Eudragit (Trade Mark).
Preferably, the film coat comprises a mixture of the water insoluble material and a water soluble material. The ratio of water insoluble to water soluble material is de~ermined by, amongst other factors, the release rate required and the solubility charac~eris~ics of the materials selected.
The water soluble material may be, for example, polyvinylpyrrolidone or, which is preferred, a water soluble cellulose, especially h~droxypropylmethyl cellulose.
Suitable combinations of water insoluble and water soluble materials for the film coat include shellac and . ~ . . . .
~ .
9 ~ ?d~3 7~G ~ ~
polyvinylpyrrolidone or, which is preferred, ethyl cellulose and hydroxypropylmethyl cellulose.
In order to facilitate the preparation of a solid, controlled release, oral dosage form according to this invention there is provided, in d further aspect of the present invention, a process for the preparation of a solid, controlled release, oral dosage form according to the present invention comprising incorporating hydromorphone or a salt thereof in a controlled re1ease matrix. Incorporation in the matrix may be effected, for example, by (a) forming granules comprising at least one water soluble hydroxyalkyl cellulose and hydromorphone or a hydromorphone salt, (b) mixing the hydroxyalkyl cellulose containing granules with at least one CI2-C3b aliphatic alcohol, and (c) optionally, compressing and shaping the granules, Preferably, the granules are formed by wet granulating the hydroxyalkyl cellulose/hydromorphone with water. In a particularly preferred embodiment of this process, the amount of water added during the wet granulation step is preferably between 1.5 and 5 times, especially be~ween 1.75 and 3.5 ~imes, the dry weight of the hydroxyalkylcellulose.
The present solid, controlled release, oral dosage form may also be prepared, in the form of film coated spheroids, by (a) blending a mixture comprising hydromorphone or a hydromorphone salt and a non-water soluble spheronising agent, ~25~ ,S
(b) extruding the blended mixture to give an extrudate, (c) spheronising the extrudate until spheroids are formed, and (d) coating the spheroids with a film coat.
Tne present solid, controlled release, oral dosage form and processes for its preparation w;ll now be described by way of example only.
Exampl_ Hydromorphone hydrochloride (4.0gm) was wet granulated with lactose monohydrate (167.0gm) and hYdroxYethYl cellulose ~40.0gm; Natrosol 250 ~X, Trade Mark) and the granules were sieved through a 12 mesh screen. The granules were then dried in a Fluid Bed Dryer at 50C and passed through a 16 mesh screen.
To the warmed hydromorphone containing granules was added molten cetostearyl alcohol (120.0gm) and the whole was mixed thoroughly. ~he mixture was allowed to cool in the air, regranulated and sieved through a 16 mesh screen.
Purified Talc ~6.0gm) and magnesium stearate (3.0gm) were then added and mixed with ~he granules. The granules were then compressed into 1000 tablets each containing, mg/tablet Hydromorphone Hydrochloride 4.0 Lactose Monohydrate 167.0 Hydrox~ethylcellulose 40.0 Cetostearyl alcohol 120.0 , .
. . ~ ~ ~ .. . .
.
:
~ 7 ~2 S
Purified Talc 6.0 Magne-sium stearate 3.
Example 2 The procedure of Example 1 was followed, but with reduced quantities of cellulose and fatty alcohol, to give 1000 tablets each containing, ~_~ab!et Hydromorphone Hydrochloride 4.0 Anhydrous Lactose 167.0 Hydroxyethylcellulose 30.0 Cetostearyl Alcohol ~0.0 Purified Talc ~.0 Magnesium Stearate 3.0 Example 3 Hydromorphone hydroehloride (4.09m~ was wet granulated wi~h lactose monohydrate (30.0gm) hydroxyethyl cellulose ~lO.Ogm;
Natrosol 250 HX, Trade Mark) and mæthacrylic acid copolymer (30.0gm, Eudragit L-1~0-55; Trade Mark) and the granules were sieved through a 12 mesh screen. The granules were then dried in a Fluid Be~ Dryer at 50C and passed through a 16 mesh screen.
To the warmed hydromorphone containing granules was added molten cetostearyl alcohol (30.0gm) and the whole was mixed thoroughly. The~mixture was allowed to cool in ~he air, regranulated and sieved through a 16 mesh screen.
The granules were then compressed into 1000 table~s each containing, ,;
: -~ 7 m~/tablet Hydromorphone Hydrochloride 4.0 Lactose Monohydrate 30.0 Hydroxyethylcellulose 10.0 Methacrylic Acid Copolymer 30.0 Cetostearyl alcohol 30.0 Examp_e 4 Hydromorphone hydrochloride (509) microcrystalline ce11ulose ~Avicel PH101, 440g) and hydroxypropylmethyl ce11ulose (Methocel E15, 109) were dry mixed. Water (350ml) was then added and the mixture was granulated. The granulated mass was extruded through a lmm cylinder and the extrudate was spheronised. The resultant spheroids were dried at 60C in a fluid bed drier. The moisture content of the drled spheroids was found to be 4.3~ w/w (Karl-Fischer). The dried spheroids were then sieved and the sieve fraction between 1.0mm and 1.4mm was retained.
The spheroids were co~ted with a film coat, having the formulation given below, to a level of 15~ w/w.
Film Coat Formulation Ethylcellulose N10 ~ 4.0X w/v Hydroxypropylmethylcellulose (Methocel E15) 1.0~ w/v Propylene glycol BP 0.5X w/v Opaspray K-1-4132 3.0~ w/v Methanol 60.0X v/v Dichloromethan2 to lQ0.0~ v/v Tt~le- tha~
, .
3~
In Vitro Dissolution Studies _ _ In vitro dissolution studies were conducted on tablets prepared as described in Example 1. The dissolution method was the USP Paddle Method described in US Pharmacopoeia XX1 (1985). The paddle speed was 100 rpmt the temperature was 37C and the medium was 900ml water.
Results are given in Table 1.
Time (hr) wt. ~ Hydromorphone re?eased 1 28.3 2 41.8 3 51.5 4 59.5 S 65.5 6 70.0 7 75.0 8 80.0 In vitro dissolution studies were conducted on tablets prepared as described in Example 2. The dissolu~ion method was the USP Paddle Method described in US Pharmacopoeia XXI
(19~5). The paddle speed was 100rpm, the temperature was 37C
and the medium was an aqueous buffer (pH 6.5).
Results are given in Table 2.
.
- ', ' ~ ' .
:
.
14 ~ 7 Time (hr) wt. ~ Hydromorphone released In vitro dissolution studies were conducted on tablets prepared as described in Example 3. The dissolution method was the USP Paddle Method described in US Pharmaoopoeia XXI
(1985). The paddle speed was 100 rpm, the temperature was 37C and the medium was 900 ml water.
Results are given in Table 3.
Table 3 Time (hr) wt. ~ Hydromorphone released : 1 35 4 66 :
: 5 ~2 ~ 76 : : 7 80 :
;
:
.
.. .
-.
. ~: :
, ~ 7~
In vitro dissolution studies were conducted on tablets prepared as described in Example 1. The dissolution method was the USP Paddle Method described in US Pharmacopoeia XXI
(1985). The paddle speed was 100rpm, the temperature was 37C
and the media were USP Buffers (pH 1.6, 6.5 and 7.2).
Results are given in Table 4.
Ti~e ~hr) w~% Hydromorphone released pH 1.6 pH 6.5 1 34.7 36.0 36.6 2 48.1 51.2 51.0 3 58.~ 61.7 61.1 4 66~5 70.0 69.8 6 79.1 81.8 81.
8 88.2 90.6 gO.7 95.1 97.7 99.2 12 100.0 100.0 100.0 Olinical Studies A. A single dose, randomised, compara~ive, pharmacokinetic study was conducted on 4 subjects employing, i) A hydromorphone hydrochloride tablet prepared as described in Example 1, (a 4mg dose), and ii) A normal release hydromorphone hydrochloride tablet (Dilaudid; Trade Mark; a 4mg dose).
, : ' .: ..
.
:: ' ~ ~7~`~25 Analysis of the plasma samples for hydromorphorle was performed by a double antibody radioimmunoassay.
Plasma was assayed by incubating first with 1251odohydromorphone and antimorphine antiserum (raised in goats against a 6-hemisuccinyl morphine-BSA conjugate), and subsequently with a solid phase bound antiserum suspension (Sac Cel, anti sheep/goat, Trade Mark). Following the addition of water the samples were centrifuged and the supernatant was removed. The radioactivity in the remaining pellet was counted on a multi-gamma counter for ~0 seconds.
Results are given in Table 5.
Time (hr) Mean Plasma Conc. (ng/ml~l) Examp!e l Dilaudid 0.50 0.9 9.4 1.0 3.8 8.8 1.50 4.4 8.6 2.0 4.2 7.8 2.5 4.5 7.9 3.0 4.8 6.2 4.0 ~.3 3.5 6.0 3.0 3.2 8.0 1.4 1.6 10.0 1.6 1.0 12.0 1.0 0.5 24.0 1.1 0.5 B. A single dose, randomised, comparative, pharmacokinetic study was conducted on 12 subjects employing.
- - ~
' . ~ .
.
i) A hydromorphone hydrochloride tablet prepared as described in Example 1 (a 4mg dose), and ii) A normal release hydromorphone hydrochloride tablet (Dilaudid; Trade Mark; a 4mg dose).
Analysis of the plasma samples for hydromorphone was performed by the radioimmunoassay described in study A. Results are given in Table 6.
Mean Plasma Conc. (ng/ml) Time (hr) Example 1 Dilaudid 0.5 2.3 5.8 1.0 3.7 7.0 1.5 3.9 7.3 : 2.0 4.4 6.4 2.5 4.5 5.9 3.0 4.3 5.3 4.0 4.3 4.4 6.0 3.7 3.1 8.0 3.1 2.5 10.0 2.5 2.3 12.0 2.1 2.0 24.0 1.4 1. 1 : C. A single dose, comparative, pharmacokinetic study was ~ ~ conducted on 24 subjec~ts employing9 : (i) A hydromorphone hydrochloride tablet prepared as ~ : described in Example I (a 4mg dose) and, .
: :
. ~ : , , , , , 37~2~
(ii) A normal release hydromorphone hydrochloride tablet (Dilaudid, Trade Mark, a 4mg dose).
Analysis of the plasma samples for hydromorphone was performed and the results are given in Table 7.
Time (hr) Mean Plasma Concn. tng!ml~
.. . _ _._ Example 1 Dilaudid 0 0.12 0.15 0-5 ~.57 2.6 1.0 0.67 2.23 1.5 0.74 1.7 2.0 0.75 1.47 2.5 0.72 1.11 3.0 0.69 0.94 3.5 0.65 0.82 4.0 0,59 0.77 5.0 0.71 0.53 6.0 0.5g 0.40 8.0 0.40 0.29 10.0 0.49 0.26 .
~. .
.
. .
i . , ~
In Vitro Dissolution Studies _ _ In vitro dissolution studies were conducted on tablets prepared as described in Example 1. The dissolution method was the USP Paddle Method described in US Pharmacopoeia XX1 (1985). The paddle speed was 100 rpmt the temperature was 37C and the medium was 900ml water.
Results are given in Table 1.
Time (hr) wt. ~ Hydromorphone re?eased 1 28.3 2 41.8 3 51.5 4 59.5 S 65.5 6 70.0 7 75.0 8 80.0 In vitro dissolution studies were conducted on tablets prepared as described in Example 2. The dissolu~ion method was the USP Paddle Method described in US Pharmacopoeia XXI
(19~5). The paddle speed was 100rpm, the temperature was 37C
and the medium was an aqueous buffer (pH 6.5).
Results are given in Table 2.
.
- ', ' ~ ' .
:
.
14 ~ 7 Time (hr) wt. ~ Hydromorphone released In vitro dissolution studies were conducted on tablets prepared as described in Example 3. The dissolution method was the USP Paddle Method described in US Pharmaoopoeia XXI
(1985). The paddle speed was 100 rpm, the temperature was 37C and the medium was 900 ml water.
Results are given in Table 3.
Table 3 Time (hr) wt. ~ Hydromorphone released : 1 35 4 66 :
: 5 ~2 ~ 76 : : 7 80 :
;
:
.
.. .
-.
. ~: :
, ~ 7~
In vitro dissolution studies were conducted on tablets prepared as described in Example 1. The dissolution method was the USP Paddle Method described in US Pharmacopoeia XXI
(1985). The paddle speed was 100rpm, the temperature was 37C
and the media were USP Buffers (pH 1.6, 6.5 and 7.2).
Results are given in Table 4.
Ti~e ~hr) w~% Hydromorphone released pH 1.6 pH 6.5 1 34.7 36.0 36.6 2 48.1 51.2 51.0 3 58.~ 61.7 61.1 4 66~5 70.0 69.8 6 79.1 81.8 81.
8 88.2 90.6 gO.7 95.1 97.7 99.2 12 100.0 100.0 100.0 Olinical Studies A. A single dose, randomised, compara~ive, pharmacokinetic study was conducted on 4 subjects employing, i) A hydromorphone hydrochloride tablet prepared as described in Example 1, (a 4mg dose), and ii) A normal release hydromorphone hydrochloride tablet (Dilaudid; Trade Mark; a 4mg dose).
, : ' .: ..
.
:: ' ~ ~7~`~25 Analysis of the plasma samples for hydromorphorle was performed by a double antibody radioimmunoassay.
Plasma was assayed by incubating first with 1251odohydromorphone and antimorphine antiserum (raised in goats against a 6-hemisuccinyl morphine-BSA conjugate), and subsequently with a solid phase bound antiserum suspension (Sac Cel, anti sheep/goat, Trade Mark). Following the addition of water the samples were centrifuged and the supernatant was removed. The radioactivity in the remaining pellet was counted on a multi-gamma counter for ~0 seconds.
Results are given in Table 5.
Time (hr) Mean Plasma Conc. (ng/ml~l) Examp!e l Dilaudid 0.50 0.9 9.4 1.0 3.8 8.8 1.50 4.4 8.6 2.0 4.2 7.8 2.5 4.5 7.9 3.0 4.8 6.2 4.0 ~.3 3.5 6.0 3.0 3.2 8.0 1.4 1.6 10.0 1.6 1.0 12.0 1.0 0.5 24.0 1.1 0.5 B. A single dose, randomised, comparative, pharmacokinetic study was conducted on 12 subjects employing.
- - ~
' . ~ .
.
i) A hydromorphone hydrochloride tablet prepared as described in Example 1 (a 4mg dose), and ii) A normal release hydromorphone hydrochloride tablet (Dilaudid; Trade Mark; a 4mg dose).
Analysis of the plasma samples for hydromorphone was performed by the radioimmunoassay described in study A. Results are given in Table 6.
Mean Plasma Conc. (ng/ml) Time (hr) Example 1 Dilaudid 0.5 2.3 5.8 1.0 3.7 7.0 1.5 3.9 7.3 : 2.0 4.4 6.4 2.5 4.5 5.9 3.0 4.3 5.3 4.0 4.3 4.4 6.0 3.7 3.1 8.0 3.1 2.5 10.0 2.5 2.3 12.0 2.1 2.0 24.0 1.4 1. 1 : C. A single dose, comparative, pharmacokinetic study was ~ ~ conducted on 24 subjec~ts employing9 : (i) A hydromorphone hydrochloride tablet prepared as ~ : described in Example I (a 4mg dose) and, .
: :
. ~ : , , , , , 37~2~
(ii) A normal release hydromorphone hydrochloride tablet (Dilaudid, Trade Mark, a 4mg dose).
Analysis of the plasma samples for hydromorphone was performed and the results are given in Table 7.
Time (hr) Mean Plasma Concn. tng!ml~
.. . _ _._ Example 1 Dilaudid 0 0.12 0.15 0-5 ~.57 2.6 1.0 0.67 2.23 1.5 0.74 1.7 2.0 0.75 1.47 2.5 0.72 1.11 3.0 0.69 0.94 3.5 0.65 0.82 4.0 0,59 0.77 5.0 0.71 0.53 6.0 0.5g 0.40 8.0 0.40 0.29 10.0 0.49 0.26 .
~. .
.
. .
i . , ~
Claims (47)
1. A process for the preparation of a solid, controlled release, oral dosage form comprising incorporating a therapeutically effective amount of hydromorphone or a salt thereof in a matrix wherein the dissolution rate in vitro of the dosage form, when measured by the USP Paddle Method at 100rpm in 900ml aqueous buffer (pH between 1.6 and 7.2) at 37°C is between 12.5% and 42.5% (by wt) hydromorphone released after 1 hour, between 25% and 55% (by wt) hydromorphone released after
2 hours, between 45% and 75% (by wt) hydromorphone released after 4 hours and between 55% and 85% (by wt) hydromorphone released after 6 hours, the in vitro release rate being independent of pH between pH 1.6 and 7.2 and chosen such that the peak plasma level of hydromorphone obtained in vivo occurs between 2 and 4 hours after administration of the dosage form.
2. A process according to claim 1 wherein the in vitro dissolution rate is between 17.5% and 37.5% (by weight) hydromorphone released after 1 hour, between 30% and 50% (by weight) hydromorphone released after 2 hours, between 50% and 70% (by weight) hydromorphone released after 4 hours and between 65% and 80% (by weight) hydromorphone released after 6 hours.
2. A process according to claim 1 wherein the in vitro dissolution rate is between 17.5% and 37.5% (by weight) hydromorphone released after 1 hour, between 30% and 50% (by weight) hydromorphone released after 2 hours, between 50% and 70% (by weight) hydromorphone released after 4 hours and between 65% and 80% (by weight) hydromorphone released after 6 hours.
3. A process according to claim 2 wherein the in vitro dissolution rate is between 22.5% and 32.5% by weight) hydromorphone released after 1 hour, between 35% and 45% (by weight) hydromorphone released after 2 hours, between 55% and 65% (by weight) hydromorphone released after 4 hours and between 65% and 75% (by weight) hydromorphone released after 6 hours.
4. A process according to any one of claims 1, 2 or 3 wherein the peak plasma level of hydromorphone occurs between 2.25 and 3.75 hours after administration of the dosage form
5. A process according to any one of claims 1, 2 or 3 wherein a therapeutically effective amount of a hydromorphone salt comprises between 2 and 50mg of hydromorphone hydrochloride.
6. A process according to any one of claims 1, 2 or 3 wherein a therapeutically effective amount of a hydromorphone salt comprises between 2 and 40mg of hydromorphone hydrochloride.
7. A process according to claim 1 wherein the matrix comprises a controlled release matrix comprising at least one water soluble hydroxyalkylcellulose, at least one C12 to C36 aliphatic alcohol and, optionally, at least one polyalkylene glycol.
8. A process according to claim 7 wherein the at least one water soluble hydroxyalkylcellulose comprises a hydroxy C1-C6 alkyl cellulose.
9. A process according to claim 8 wherein the at least one hydroxyalkyl cellulose comprises hydroxypropyl cellulose, hydroxypropylmethylcellulose or hydroxyethylcellulose.
10. A process according to claim 9 wherein the at least one hydroxyalkylcellulose comprises hydroxyethylcellulose.
11. A process according to claim 7 wherein the dosage form contains between 5% and 25% (by weight) of the at least one hydroxyalkylcellulose.
12. A process according to claim 11 wherein the dosage form contains between 6.25% and 15% (by weight) of the at least one hydroxyalkylcellulose.
13. A process according to claim 7 wherein the aliphatic alcohol comprises a C14 to C22 aliphatic alcohol.
14. A process according to claim 7 wherein the aliphatic alcohol comprises lauryl alcohol, myristyl alcohol, stearyl alcohol, cetyl alcohol or cetostearyl alcohol.
15. A process according to claim 14 wherein the aliphatic alcohol comprises cetyl alcohol or cetostearyl alcohol.
16. A process according to claim 7 wherein the dosage form contains between 20% and 50% (by weight) of the at least one fatty alcohol or of the at least one fatty alcohol and the at least one polyalkylene glycol.
17. A process according to claim 16 wherein the dosage form contains between 25% and 45% (by weight) of the at least one fatty alcohol or of the at least one fatty alcohol and the at least one polyalkylene glycol.
18. A process according to claim 7 wherein the ratio of the at least one hydroxyalkylcellulose to the at least one aliphatic alcohol/polyalkylene glycol is between 1:2 and 1:4.
19. A process according to claim 18 wherein the ratio is between 1:3 and 1:4.
20. A process according to claim 1 comprising (a) wet granulating at least one water soluble hydroxyalkylcellulose with hydromorphone or a salt thereof to form granules, (b) mixing the hydroxyalkylcellulose containing granules with at least one C12-C36 aliphatic alcohol, and (c) optionally, compressing and shaping the granules.
21. A process according to claim 20 wherein the at least one water soluble hydroxyalkylcellulose and the hydromorphone or the salt thereof are wet granulated with water, the weight ratio of the water to the dry weight of the at least one water soluble hydroxyalkylcellulose being between 1.5 to 1 and 5 to 1.
22. A process according to claim 21 wherein the weight ratio of the water to the dry weight of the at least one water soluble hydroxyalkylcellulose is between 1.75 to 1 and 3.5 to 1.
23. A process according to clairn 1 comprising blending a mixture comprising hydromorphone or a salt thereof and a non-water soluble spheronising agent, extruding the blended mixture to give an extrudate spheronising the extrudate until spheroids are formed and coating the spheroids with a film coat.
24. A process according to claim 23 wherein the non-water soluble spheronising agent comprises microcrystalline cellulose.
25. A solid, controlled release, oral dosage form whenever prepared by a process according to any one of claims l, 2 or 3.
26. A solid, controlled release, oral dosage form, the dosage form comprising a therapeutically effective amount of hydromorphone or a salt thereof in a matrix wherein the dissolution rate in vitro of the dosage form, when measured by the USP Paddle Method at 100rpm in 900ml aqueous buffer (pH between 1.6 and 7.2) at 37°C is between 12.5% and 42.5% (by wt) hydromorphone released after 1 hour, between 25% and 55% (by wt) hydromorphone released after 2 hours, between 45% and 75% (by wt) hydromorphone released after 4 hours and between 55% and 85% (by wt) hydromorphone released after 6 hours, the in vitro release rate being independent of pH between pH 1.6 and 7.2 and chosen such that the peak plasma level of hydromorphone obtained in vivo occurs between 2 and 4 hours after administration of the dosage form.
27. A dosage form according to claim 26 wherein the in vitro dissolution rate is between 17.5% and 37.5% (by weight) hydromorphone released after 1 hour, between 30% and 50% (by weight) hydromorphone released after 2 hours, between 50% and 70% (by weight) hydromorphone released after 4 hours and between 60% and 80% (by weight) hydromorphone released after 6 hours.
28. A dosage form according to claim 27 wherein the in vitro dissolution rate is between 22.5% and 32.5% (by weight) hydromorphone released after 1 hour, between 35% and 45% (by weight) hydromorphone released after 2 hours, between 55% and 65% (by weight) hydromorphone released after 4 hours and between 65% and 75% (by weight) hydromorphone released after 6 hours.
29. A dosage form according to any one of claims 26, 27 or 28 wherein the peak plasma level of hydromorphone occurs between 2.25 and 3.75 hours after administration of the dosage form.
30. A dosage form according to any one of claims 26, 27 or 28 wherein a therapeutically effective amount of a hydromorphone salt comprises between 2 and 50mg of hydromorphone hydrochloride.
31. A dosage form according to any one of claims 26, 27 or 28 wherein a therapeutically effective amount of a hydromorphone salt comprises between 2 and 40mg of hydromorphone hydrochloride.
32. A dosage form according to claim 26 wherein the matrix comprises a controlled release matrix comprising at least one water soluble hydroxyalkylcellulose, at least one C12 to C36 aliphatic alcohol and, optionally, at least one polyalkylene glycol.
33. A dosage form according to claim 32 wherein the at least one water soluble hydroxyalkylcellulose comprises a hydroxy C1-C6 alkyl cellulose.
34. A dosage form according to claim 33 wherein the at least one hydroxyalkyl cellulose is selected from hydroxypropyl cellulose, hydroxypropylmethylcellulose and hydroxyethylcellulose.
35. A dosage form according to claim 34 wherein the at least one hydroxyalkylcellulose comprises hydroxyethylcellulose.
36. A dosage form according to claim 32 wherein the dosage form contains between 5X and 15% (by weight) of the at least one hydroxyalkylcellulose.
37. A dosage form according to claim 36 wherein the dosage form contains between 6.25% and 15% (by weight) of the at least one hydroxyalkylcellulose.
38. A dosage form according to claim 32 wherein the aliphatic alcohol comprises d C14 to C22 aliphatic alcohol.
39. A dosage form according to claim 32 wherein the aliphatic alcohol is selected from lauryl alcohol, myristyl alcohol, stearyl alcohol, cetyl alcohol and cetostearyl alcohol.
40. A dosage form according to claim 39 wherein the aliphatic alcohol is selected from cetyl alcohol and cetostearyl alcohol.
41. A dosage form according to claim 32 wherein the dosage form contains between 20% and 50% (by weight) of the at least one fatty alcohol or of the at least one fatty alcohol and the at least one polyalkylene glycol.
42. A dosage form according to claim 41 wherein the dosage form contains between 25% and 45% (by weight) of the at least one fatty alcohol or of the at least one fatty alcohol and the at least one polyalkylene glycol.
43. A dosage form according to claim 32 wherein the ratio of the at least one hydroxyalkylcellulose to the at least one aliphatic alcohol/polyalkylene glycol is between 1:2 and 1:4.
44. A dosage form according to claim 43 wherein the ratio is between 1:3 and 1:4.
45. A dosage form according to claim 26 in the form of film coated spheroids wherein the spheroid matrix comprises a non-water soluble spheronising agent.
46. A dosage form according to claim 45 wherein the spheroid matrix comprises microcrystalline cellulose.
47. A dosage form according to claim 46 wherein the spheroid matrix comprises microcrystalline cellulose and a water insoluble polymer.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB868626098A GB8626098D0 (en) | 1986-10-31 | 1986-10-31 | Controlled release hydromorphone composition |
| GB8626098 | 1986-10-31 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1297025C true CA1297025C (en) | 1992-03-10 |
Family
ID=10606640
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000550717A Expired - Lifetime CA1297025C (en) | 1986-10-31 | 1987-10-30 | Controlled release hydromorphone composition |
Country Status (12)
| Country | Link |
|---|---|
| US (2) | US4844909A (en) |
| EP (1) | EP0271193B1 (en) |
| JP (1) | JP2806385B2 (en) |
| AT (1) | ATE67933T1 (en) |
| AU (1) | AU600765B2 (en) |
| CA (1) | CA1297025C (en) |
| DE (1) | DE3773468D1 (en) |
| DK (1) | DK175139B1 (en) |
| ES (1) | ES2038673T3 (en) |
| GB (2) | GB8626098D0 (en) |
| IE (1) | IE60495B1 (en) |
| ZA (1) | ZA878018B (en) |
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- 1987-10-22 AT AT87309333T patent/ATE67933T1/en not_active IP Right Cessation
- 1987-10-22 GB GB8724705A patent/GB2196848B/en not_active Expired - Fee Related
- 1987-10-22 DE DE8787309333T patent/DE3773468D1/en not_active Expired - Lifetime
- 1987-10-22 EP EP87309333A patent/EP0271193B1/en not_active Expired - Lifetime
- 1987-10-26 ZA ZA878018A patent/ZA878018B/en unknown
- 1987-10-26 US US07/113,865 patent/US4844909A/en not_active Expired - Lifetime
- 1987-10-30 IE IE292487A patent/IE60495B1/en not_active IP Right Cessation
- 1987-10-30 JP JP62275558A patent/JP2806385B2/en not_active Expired - Lifetime
- 1987-10-30 AU AU80524/87A patent/AU600765B2/en not_active Expired
- 1987-10-30 CA CA000550717A patent/CA1297025C/en not_active Expired - Lifetime
- 1987-10-30 DK DK198705686A patent/DK175139B1/en not_active IP Right Cessation
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1989
- 1989-04-28 US US07/345,354 patent/US4990341A/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| GB2196848B (en) | 1990-11-14 |
| DK568687D0 (en) | 1987-10-30 |
| US4990341A (en) | 1991-02-05 |
| DK568687A (en) | 1988-05-01 |
| DK175139B1 (en) | 2004-06-14 |
| ZA878018B (en) | 1988-04-29 |
| DE3773468D1 (en) | 1991-11-07 |
| EP0271193A3 (en) | 1988-07-13 |
| ES2038673T3 (en) | 1993-08-01 |
| IE872924L (en) | 1988-04-30 |
| IE60495B1 (en) | 1994-07-27 |
| GB2196848A (en) | 1988-05-11 |
| US4844909A (en) | 1989-07-04 |
| JPS63122623A (en) | 1988-05-26 |
| EP0271193B1 (en) | 1991-10-02 |
| GB8626098D0 (en) | 1986-12-03 |
| GB8724705D0 (en) | 1987-11-25 |
| AU8052487A (en) | 1988-05-05 |
| AU600765B2 (en) | 1990-08-23 |
| JP2806385B2 (en) | 1998-09-30 |
| ATE67933T1 (en) | 1991-10-15 |
| EP0271193A2 (en) | 1988-06-15 |
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