CN1102323A

CN1102323A - Sustained release compositions and a method of preparing pharmaceutical compositions

Info

Publication number: CN1102323A
Application number: CN94106701A
Authority: CN
Inventors: J·希菲尔德; T·J·克诺特; S·T·莱斯利; S·T·A·马尔考斯卡; R·B·米勒; D·A·普雷特; K·J·史密夫; M·查辛; P·戈登海姆; 小·F·佩迪; R·萨克勒; B·奥斯拉克
Original assignee: European Celtic
Current assignee: European Celtic; Euro Celtique SA
Priority date: 1993-07-01
Filing date: 1994-07-01
Publication date: 1995-05-10
Anticipated expiration: 2014-07-01
Also published as: CN1230154C

Abstract

Sustained release pharmaceutical formulations containing morphine, or a pharmaceutically acceptable salt thereof, as active ingredient, suitable for administration on a once daily basis, are disclosed. It is suitable for taking orally and gives a peak plasma level at 1.0 to 6 hours after administration, characterized in that, the formulation provides a W50 for the M-6-G metabolite for morphine of between 4 and 12 hours. It relates to the preparation of the dosage and the pharmaceutically acceptable salt releasing particles.

Description

Sustained release compositions and a method of preparing pharmaceutical compositions

The present invention relates to improve slow releasing composition, more particularly, but the present invention relates to contain the slow release oral unit dosage form that morphine or its pharmaceutically acceptable salt are made active component.

But the present invention also briefly relates to the preparation method of peroral dosage form, but the multiple granule of the preferred sustained-release granular formulation of described peroral dosage form/multiple granule (multiparticulates) and compacting, and for example diameter is at the multiple granule of 0.1-3.0mm scope; The inventive method provides multiple granule with beyond thought high yield.

Morphine is an Opium class analgesics, can be used for treating pain, especially alleviates violent pain.Contain the compositions of slow release form of morphine at present commercially available be so-called " twice on the one " preparation, promptly active sustainable 12 hours of said preparation or longer time, therefore need obey twice every day.

But an object of the present invention is to provide the slow release oral unit dosage form that contains morphine, the effective active persistent period of this dosage form is 24 hours or longer time, therefore is suitable for taking once every day.

According to the present invention, have surprisingly been found that: continued 24 hours or effective therapeutic activity of longer time can get the slow releasing preparation of self-contained morphine, said preparation at a good pace reaches peak plasma concentration in the body after taking; Promptly reached peak plasma concentration in the body in 1.0 to 6 hours taking the back, preferred 1 to 4 hour, for example 1 to 3.5 hour.

Therefore, an embodiment of the present composition provide contain morphine or its pharmaceutically acceptable salt do active component can be oral the slow release unit dosage forms, said preparation reaches peak plasma concentration taking back 1 to 6 hour, preferred 1 to 4 hour (for example 1 to 3.5 hour).

Find:, when such dosage form is taken by single dose, in 1 to 4.25 hour, reach mid point tmax value under fasting state at one group for example among the healthy volunteer of n=5.

If take morphine and the plasma analysis method is a high performance liquid chromatography with the morphine sulfate form, the peak plasma concentration of morphine (every ml blood plasma) be preferably oral morphine sulfate amount 0.5 * 10 ^-7To 7.5 * 10 ^-7Doubly.If take morphine base or other salt except that sulfate, the preferred ratio of the thing of taking medicine and peak plasma concentration should adjust according to the molecular weight of described alkali or salt.

Should contain enough morphines or its salt according to unit dosage forms of the present invention, to obtain continuing at least 24 hours therapeutic activity.Morphine or its salt actual amount in any one concrete dosage form should depend on some variablees certainly, comprises that (ⅰ) estimates once to desire the quantity of the dosage form of taking and (ⅱ) to any concrete patient's expectation dosage any.But for simplicity, will contain 10 to 500mg morphines (by morphine sulfate), therefore, for example, contain 20,30,60,90,120,150 and 200mg morphine (by above) according to typical flat dosage form of the present invention according to unit dosage forms of the present invention.

Morphine-6-glucosiduronic acid (following for M-6-G) is the metabolite of a known morphine, and itself just has strong analgesic property, described analgesic property at least can with the comparing of morphine.

According to another aspect of the present invention, we find, the characteristics that contain effective dose morphine or its pharmaceutically acceptable salt and continue at least 24 hours effective pharmaceutical formulations are: for the W of M-6-G metabolite ₅₀Between 4 to 12 hours, and the tmax of M-6-G is preferably within 1 to 6.5 hour scope, and more preferably 3 to 6.5 hours, even more preferably 3.5 to 6 hours.

Parameter W ₅₀Be defined as the width of curve of blood plasma figure when 50%Cmax (plasma profile), promptly plasma concentration is equal to or greater than 50% o'clock persistent period of peak concentration.This parameter is measured by the linear interpolation of institute's observed data, its representative time difference between first (or unique) rising cross point and last (or unique) decline cross point in this curve of blood plasma figure.

Surprisingly, we observe, have the W of M-6-G ₅₀The characteristics of the preparation of the present invention of the characteristics within particular range also are usually: the W of morphine ₅₀Within similar scope.Therefore, according to another preferable case of the present invention, the characteristics that contain effective dose morphine or its pharmaceutically acceptable salt and continue at least 24 hours effective pharmaceutical formulations are: for the W of morphine ₅₀Between 4 to 12 hours, and preferably had tmax in the scope in 1 to 6.5 hour taking the back, more preferably 1 to 4 hour, for example 1 to 3.5 hour.

Characteristics according to the preferred formulation of this aspect of the present invention are: have above parameter when taking for patient of fasting state it.

The preferred W of M-6-G and morphine ₅₀Value about 5.5 to 12 or 5.5 to 11 or even 6 to 10 hours scope in.

The Cmax of preparation of the present invention has dose dependent.For example, the preferred embodiment that contains the 60mg morphine sulfate is characterized in that when taking with single dose form: the Cmax of M-6-G is within the scope of 65mg/ml to 150ng/ml.The characteristics of the preferred embodiment that another is such are: the Cmax of morphine is within 7.5 to 20ng/ml scope.

With a preferred embodiment as described herein, single dose is taken the back for 5 fasting trial volunteers and is found the W of morphine and M-6-G ₅₀Within 5.5 to 12 hours scope.

Have been found that, an example of such dosage unit is when giving one group to have that for example n=5 healthy volunteer takes under fasting state with single dose form, the mid point tmax value of M-6-G is in 3.5 to 6 hours scopes, for example 4 to 6.0 hours, and the mid point tmax value of morphine is in 2.5 to 5 hours scopes.

Further find according to the present invention, the peak plasma concentration time of morphine that obtains to expect and M-6-G also provides effective active at least 24 hours time, release characteristics in the body of said preparation (containing in the aqueous buffer solution (pH6.5) of 0.05%W/V Tween 80 in 37 ℃ of mensuration at 900ml in 100 rev/mins with the Ph. Eur. Basket method of improvement) is listed below preferably:

In the accompanying drawings:

Fig. 1 to 5 be 5 trial volunteers after taking preparation of the present invention, the curve of blood plasma figure of morphine among each volunteer and M-6-G.

Morphine that Fig. 6 draws for result shown in Fig. 1 to 5 and the average blood plasma curve chart of M-6-G.

Fig. 7 is the morphine that obtained with known controlled release morphine preparation and the average blood plasma curve chart of M-6-G in 9 trial volunteers.

The present composition can provide in a variety of forms, for example tablet or contain capsule, ball or the pill of particle. Described composition generally includes active component (morphine or its salt) and can be used to improve the diluent that described active component discharges. According to the present invention, the preferred form of unit dosage form comprises the capsule that multiple particle is housed, and described multiple particle mainly comprises described active component, the meltable carrier of hydrophobicity or diluent, and can comprise hydrophilic release regulator. Specifically, described multiple particle preferably prepares by such method, be that the method mainly comprises: make dry active component and the mixture of meltable controlled release material, then this mixture is carried out machining with a certain speed in super mixer, and provide enough energy to described meltable material with its fusing or softening, form thus the multiple particle that contains active component. The multiple particle that obtains is suitably sieved and cool off, obtain the multiple particle of granular size in 0.1 to 3.0mm preferred 0.25 to 2.0mm scope. This preferred and new method is described hereinafter, and it is suitable for the dosage device that industrial production contains morphine or other active material.

Find that if use such production technology, the most easily obtain required release characteristics (aforesaid body in external), the composition that wish is produced should comprise two main components, that is:

(a) active component (morphine or its salt); With

(b) the meltable carrier of hydrophobicity or diluent; Can comprise simultaneously

(c) controlled release component comprises the particle of water-soluble meltable material or solubility or insoluble organic or inorganic material.

We find that the total amount of active component can change in described composition in very wide scope, for example be 10 to 60%.

Described hydrophobicity fusible component (b) should be the hydrophobic substance such as natural or synthetic wax or oil, for example hydrogenated vegetable oil or rilanit special, and also fusing point is preferably 35 to 100 ℃, preferred 45 to 90 ℃.

The component of adjustment release (c) is if water-soluble meltable material is preferably polyethylene glycol, if particulate matter is preferably pharmaceutically acceptable material, and for example Dicalcium Phosphate or lactose.

The content of morphine low as in 10-30%(weight) between the time, need to mix the component of a small amount of adjustment release, for example 5-15%(weight) Macrogol 6000, to obtain gratifying extracorporeal releasing speed. When the medicine carrying capacity is big, 40 to 60%(weight for example), especially surprisingly, only need to mix very small amount of polyethylene glycol, for example 0.01 to 1%(weight) and, regulate extracorporeal releasing speed.

Perhaps, the controlled release mixture that morphine (or its salt) preparation (for example through dry method or wet granulation or by mixing) one-tenth can be made by the composition except low-melting constituent. The suitable material that can be included in the controlled release matrix comprises, for example:

(a) hydrophily or hydrophobic polymer, gummy class for example, cellulose ethers, the material of protein derived, polyamide fibre, crylic acid resin, PLA, polyvinyl chloride, starch, polyvinylpyrrolidone, acetic acid-O-phthalic acid cellulose. In these polymer, preferred following polymers: cellulose ethers, the cellulose ethers that especially replaces, for example alkylcellulose (for example ethyl cellulose), C₁-C ₆Hydroxy alkyl cellulose (for example hydroxypropyl cellulose, particularly hydroxyethylcellulose); And crylic acid resin (for example methyl acrylic ester, weevil base acrylic copolymer). Described controlled release matrix can suitably contain 1 to 80%(weight) between hydrophily or hydrophobic polymer.

(b) digestible replacement or unsubstituted long-chain (C₈-C ₅₀, C especially₈-C ₄₀) hydro carbons, fatty acid for example, hydrogenated vegetable oil such as Cutina(trade mark), aliphatic alcohols (for example laruyl alcohol, myristyl alcohol, octadecanol, cetanol, perhaps preferred cetostearyl alcohol), the glyceride type of aliphatic acid, glycerin monostearate for example, mineral oil and wax class (for example beeswax, glycowax, castor wax (castor wax) or Brazil wax). The preferred hydro carbons of fusing point between 25 to 90 ℃. In these long chain hydrocarbon materials, preferred fat (aliphatic series) alcohols. Described matrix can comprise be no more than 60%(weight) at least a digestible long chain hydrocarbon.

(c) polyethylene glycols. Described matrix can comprise be no more than 60%(weight) at least a polyglycols.

Suitable matrix comprises one or more cellulose ethers or acrylic resin, one or more C₁₂-C ₃₆Fatty alcohol, preferred C₁₄-C ₂₂Fatty alcohol, and/or one or more hydrogenated vegetable oils.

Specially suitable matrix comprises one or more alkylcelluloses, one or more C₁₂-C ₃₆(preferred C₁₄-C ₂₂) fatty alcohol, and can comprise one or more polyglycols.

Described matrix preferably comprises between 0.5 to 60%, 1 to 50%(weight especially) between cellulose ether.

Described acrylic resin preferred methacrylate, methacrylic acid copolymer USNF A type (Eudragit L for example, trade mark), Type B (Eudragit S, trade mark), C type (Eudragit L 100-55, trade mark), Eudragit NE 30D, Eudragit E, Eudragit RL and Eudragit RS. Described matrix preferably comprises 0.5 to 60%(weight) between, preferred 1 to 50%(weight) between acrylic resin.

During no polyglycols, described matrix preferably comprises between 1 to 40%, 2 to 36%(weight especially) between fatty alcohol. If contain polyglycols in the described peroral dosage form, then described fatty alcohol and polyglycols closes heavy 2 to the 40%(weight that preferably account for described matrix) between 2 to 36%(weight especially) between.

Described polyglycols can be a polypropylene glycol for example, or preferred Polyethylene Glycol.The number-average molecular weight of at least a polyglycols is preferably between 200 and 15000, particularly between 400 and 12000.The controlled release matrix that contains morphine can easily prepare by described active component is dispersed in the described hierarchy of control with conventional pharmaceutical technology, and described conventional pharmaceutical technology comprises for example melt granulation, wet granulation, dry mixed, dry granulation or co-precipitation.

The slow releasing preparation of another form comprises globule (spheroids), and it is by making morphine (or its salt) with nodulizer such as microcrystalline Cellulose nodularization.

The present invention also comprises the preparation method of the multiple granule of slow release that contains morphine or its salt, and it comprises:

(a) in super mixer, but to contain graininess morphine or its salt and graininess fusing point be 35 to 150 ℃ for example the mixture of the release components of 35 to 100 ℃ hydrophobic meltable carrier or diluent and optional carry out mechanization with a certain speed and handle, and import energy, thereby form agglutinator so that described carrier or diluent melt or be softening; Described release components comprises the meltable material of water solublity, perhaps graininess solubility or insoluble organic or inorganic material;

(b) agglutinator that will be bigger is pulverized to obtain controlled release kind grain; And

(c) continue mechanical treatment, add the described carrier and the diluent of low percentage amounts simultaneously again; And

(d) but repeating step (c) and possible step (b) 1 time or repeatedly as nearly 5 times.

This method can obtain the high yield multiple granule of (surpassing 80%), the multiple granule of gained is in required magnitude range, has required extracorporeal releasing speed, and rate of release homogeneous, surprisingly, when being in its preferred form, the activity that the first peak of the plasma concentration of product had 24 hours continues.

The multiple granule that obtains can be sieved to remove excessive or too small particle, then with in the hard capsule of for example packing into and make the required dosage unit of the active substance that contains required dosage.

The consumption of morphine sulfate so that in the multiple granule content of

morphine sulfate

10 and 60%(W/W) between be preferred, particularly, for the high dose product about 45 and about 60%(W/W) between, for the low dosage product between 10 and 45%.

In this method of the present invention, described medicine all, add in step (a) together with the used hydrophobic meltable controlled release material of major part.In step (a), add meltable controlled release amount of substance preferably adds the composition total amount in whole process of production 25% and 45%(W/W) between, more preferably between 30 and 40%.

The meltable controlled release amount of substance that adds once more in step (c) is preferably at 5% and 20%(W/W of adding composition total amount) between, more preferably 8% and 17%(W/W) between.

The step of described method (a) can for example be carried out in Collette Vactron 75 or the suitable blender at the conventional super mixer of band standard stainless steel inner lining.This mixture handled to bed temperature always reach more than 40 ℃.With regard to NAG hyle, the mixture that obtains has agglutinating granular texture, particle size at about 1-3mm to the scope of fine powder.Under the situation of described embodiment, the outward appearance of such material is the agglutinator sample below, when with it in temperature when cooling that is lower than 40 ℃, it has property firm in structure, can't pulverize with pointing.In this step, described agglutinator has irregular size, shape and outward appearance.

Preferably with described agglutinator cooling.Refrigerative temperature is not strict, can adopt ℃ for example temperature in 37 ℃ of scopes of room temperature of room temperature to 45 easily.

Adopt any suitable equipment that described agglutinator is pulverized.Described equipment will make excessive agglutinator pulverizing the short grained mixture of powder and the preferred following diameter of tool 2mm.Usually the preferred Comil that uses the Jackson Crockatt granulator that adopts the suitable size sieve or have a suitable dimension sieve carries out gradation.We find that if the mesh size of using is too little, then the agglutinator that melts can stop up sieve under agitator or impeller action in the said equipment, hinder further passing through of mixture, thereby output is reduced.Found 12 or bigger mesh size or 94G Comill sieve suitable.

The material of gradation sent back to continue in the described super mixer to handle.It is believed that this can make thinner particle bond become the multiple granule of uniform particle size.

In the preferred version of the inventive method, the processing of the material of gradation is continued to used hydrophobic meltable material always begin to soften/melt, add other hydrophobic meltable material then.Continue to mix until the multiple granule that this mixture is transformed into required prescribed particle size scope.

For guaranteeing that uniform energy is defeated by composition in the super mixer, preferably adopt microwave energy to provide to the described energy of small part.

Energy also can for example provide with heating jacket or impeller and chipper blade by this blender by other method.

Behind granulating, it can be sieved removing any excessive or too small material, and with its cooling or cool.

The granule of gained can be used for preparing dosage device such as tablet or capsule by known method itself.

In this method of the present invention, be chosen in the temperature of mixing channel in the whole mechanical processes, to avoid material to mixing the excessive bonding of cell wall.We find that generally with regard to the fusion temperature of described material, described temperature should be both not too high, and was also not too low, and can easily carry out optimum selection to avoid the problems referred to above to it.The method of the mixture of medicine and granular hydrophobic meltable carrier is handled in the mechanization of mentioning first above the same applies in super mixer.In for example described below method, found that groove temperature about 60 ℃ among the embodiment is gratifying, can avoid adhering on the groove.

For producing according to tablet of the present invention, can will for example mix with conventional method with required excipient (if having) by the above-mentioned multiple granule that makes with Y-Cone or hopper blender (bin-blender), and with the mixture that the obtains sheeting equipment tabletting of pressed disc method usefulness suitable size routinely.Tablet can be produced with conventional tablet machine.In the described below embodiment, tablet is produced on the one-shot F3 of standard Manesty machine or Kilian RLE 15 rotary tablet machines.

For the present invention is fully understood, only provide the following example with illustrational mode.

Embodiment 1 to 8

Having the pill of filling a prescription shown in the following table I adopts the following step to prepare:

Be that the composition of 10kg is put into 75 liters of capacity and is equipped with that variable-ratio mixes and the groove of the Collette Vactron blender (or suitable equipment) of granulation blade with gross weight (ⅰ);

(ⅱ) these compositions are mixed, heat simultaneously that material is made into ball in groove;

(ⅲ) ball is drawn off from blender and with its sieve with tell 0.5 and the 2mm aperture sieve between the ball collected.

The extracorporeal releasing speed of

embodiment

1,2,3 and 5 product with the Ph.Eur.Basket method of improvement in 100 rev/mins in 900ml aqueous buffer solution (pH6.5) in 37 ℃ of detections.For every kind of product, tested 6 pill samples, each sample contains the morphine sulfate that amounts to 30mg.

Be listed in result in the following table II and be the meansigma methods of 6 samples of every kind of product being tested.

Pharmacokinetic study in health aspiration experimenter person shows, behind the capsule of the ball of taking an

embodiment

1,2,3 who contains the morphine sulfate that is enough to provide 30mg dosage or 5, mid point between 1.0 and 3.5 hours is during the time, and the peak plasma concentration of morphine is 2.2 to 21.6ng/ml.

Embodiment 9 to 12

Having the granule of filling a prescription shown in the following table III adopts the following step to prepare:

ⅰ) composition (a) to (c) (gross weight 20kg) is put into 75 liters of capacity and be equipped with that variable-ratio mixes and the groove of the Collette Vactron blender (or suitable equipment) of granulation blade;

ⅱ) with described composition in about 150-350 rev/min mixing, heat in groove material simultaneously by coagulation;

ⅲ) make described agglutinative material, obtain controlled release kind grain by Comill and/or Jackson Crockatt gradation;

ⅳ) that the material of described gradation is warm and mix in the groove of 75 liters Collette Vactron, add composition (d) simultaneously, until to be higher than the single-size that 80% yield makes required predetermined magnitude range, this needs about 15 minutes;

ⅴ) with described granule by draw off in the blender and with its sieve with tell 0.5 and the 2mm aperture sieve between the granule collected.

Embodiment 9,10 and 11 and the extracorporeal releasing speed of the following examples 12 contain 0.05%(W/V in 100 rev/mins at 900ml with the Ph.Eur.Basket method of improvement) in the aqueous buffer solution (pH6.5) of Tween 80 in 37 ℃ of detections.For every kind of product, tested 6 particulate samples, each sample contains the morphine sulfate that amounts to 60mg.Be listed in result in the following table IV and be the meansigma methods of 6 samples of every kind of product being tested.

Repeat the program of embodiment 11, but following change is arranged: the granule of gradation adds in the cold trap of Collette Vactron, adds composition (d) and mixing then, during mixing with chuck heating and microwave heating.Provided rate of release in the body among the table IV a, it shows, although embodiment 11 is identical with the composition of 12 products, handles difference and then causes rate of release to change.

To mix and be used for filled hard capsules according to the granule that embodiment 9 to 12 produces separately with purified talc and magnesium stearate, and make each capsule contain the 60mg morphine sulfate.With prepared capsule be used for open type, at random the exchange (open, randomised crossover) pharmacokinetic study.As the part of these researchs, patient takes a capsule of the present invention after overnight fasted, perhaps takes a slice 30mg MST CONTINUS ^RSheet (semidiurnal preparation).From the not current limliting body picked-up in back 4 hours of taking medicine.Take medicine and supplied with the low fat lunch in back 4 hours.Supplied with dinner in back 10 hours in taking medicine, and at the back 13.5 hours supply snacks of taking medicine.Do not give other food until the back 24 hours blood samplings of taking medicine.At following time blood sampling: the back 1,1.5,2,2.5,3,3.5,4,5,6,9,12,18,24,36,48 and 72 hour of taking medicine.

Carry out pharmacokinetic study with these capsules, take medicine according to above agreement and blood sampling after mid point time between 2 and 6 hours, obtain the peak plasma concentration of the morphine of 3.2-29.2ng/ml.

Containing the particulate capsule that makes according to

embodiment

10 and 12 has provided respectively at mid point tmax4 hour mean Cmax 11.9ng/ml with in mean Cmax 9.2ng/ml(these values individual Cmax of representative of mid point tmax2.5 hour and the meansigma methods of tmax value).By contrast, take MSTCONTINUS The patient's of sheet Cmax and tmax are respectively 10.6-11.4ng/ml and 2.0-2.5 hour.Yet, find, accept the capsular patient of the present invention in the time of 24 hours in the blood plasma concentration ratio of morphine accept MST CONTINUS

The concentration height of the patient of sheet in the time of 12 hours.

Based on the granule that makes among the embodiment 9 and at morphine and morphine-6-glucosiduronic acid, under fasting state, carry out pharmacokinetic study after 5 trial volunteers are taken a capsule that contains the 60mg morphine sulfate.The results are shown in Table V and Fig. 1 to 6.

And having shown 9 healthy volunteers, Fig. 7 under identical experimental condition, takes known twice on the one morphine sulfate preparation MST CONTINUS of containing

And with the average blood plasma curve chart that obtains behind the identical analytical blood sample, described identical experimental condition is meant identical with employed experimental condition and analytical method in the test of carrying out with preparation of the present invention with identical analytical method.V and Fig. 1 to 6 are shown in the results are shown in that this test draws.As can be seen, MST CONTINUS The M-6-G that produced in the time of 12 hours and the mean plasma concentration of morphine are respectively about 14ng/ml and 2ng/ml; The plasma concentration meansigma methods 24 hours time that obtains with preparation of the present invention is M-6-G 17.5ng/ml and morphine 2.5ng/ml as shown in Figure 6.

Embodiment 13

By preparing granule with embodiment 9 to 12 similar methods, but described granule contains following ingredients:

Weight %

Morphine sulfate 55.0

Hydrogenated vegetable oil 44.7

Polyethylene glycol 6000 0.3

Then described particulate samples is mixed with Y-Cone or hopper mixer by two batches (1 and 2) with magnesium stearate and purified talc, each uses one-shot F3Manesty tablet machine tabletting on the common concave surface equipment of 7.1mm diameter with mixed mixture then.The component content of every dosage unit is as follows:

Table VI
			The sheet composition	The Mg/ sheet
1 2
		Morphine sulfate		60.00	60.00
Hydrogenated vegetable oil	48.77		48.77
		Polyethylene Glycol		0.33	0.33
Subtotal	109.1		109.1
		Magnesium stearate		1.42	2.0
Purified talc	2.18		3.0

Measure the not dissolving of tabletting particulate samples (every sample contains the 60mg morphine sulfate) with the Ph.Eur.Basket method of aforementioned improvement.For the dissolving of this tablet, replace Ph. Eur. Basket method with the Ph.Eur.Paddle method.The results are shown in the following table VII.

NR=is record not

Above result shows that tabletting can significantly reduce the rate of release of active component.

Embodiment 14

Repeat the program of embodiment 13, but following change is arranged.

Granule is made by following ingredients:

Weight %

Morphine sulfate 55.0

Hydrogenated vegetable oil 44.4

Polyethylene glycol 6000 0.6

Adopt 7.1mm diameter concave surface instrument preparation two batches of tablets (3 and 4) with described granule.The composition of every dosage unit is as follows:

Table Ⅷ
			The sheet composition	The Mg/ sheet
3	4
		Morphine sulfate	60.0	60.0
Hydrogenated vegetable oil	48.44				48.44
		Polyethylene glycol 6000	0.655	0.655
Subtotal	109.1				109.1
		Poloxamer188	-	5.0
Magnesium stearate	2.0				2.0
		Purified talc	3.0	3.0

Measure this tablet and the not dissolving of tabletting particulate samples (every sample contains the 60mg morphine sulfate) with preceding method.The results are shown in the following table IX.

These results show that once more the granule tabletting significantly reduces the speed of disengaging of morphine sulfate;

Comparative tablet

3 and 4 rate of release also can be found out: using surfactant (is Poloxamer 188 here ) make the tabletting excipient and can regulate described rate of release, contain the height of the rate of release of this surfactant 4 than the tablet 3 that does not contain this surfactant.

Claims

1, a kind of can be oral contain the slow release unit dosage forms that morphine or its pharmaceutically acceptable salt are made active component, said composition provided peak plasma concentration in 1.0 to 6 hours taking the back.

2, according to the medicinal unit dosage forms of claim 1, said composition provided peak plasma concentration in 1.0 to 3.5 hours taking the back.

3, a kind of slow-releasing medicated preparation, it contains effective dose morphine or its pharmaceutically acceptable salt and 24 hours effectively, and described pharmaceutical formulation is characterised in that: the W of M-6-G metabolite ₅₀(definition as described above) is between 4 and 12 hours.

4, a kind of slow-releasing medicated preparation, it contains effective dose morphine or its pharmaceutically acceptable salt, and at least 24 hours effectively, described pharmaceutical formulation is characterised in that: the W of morphine ₅₀(definition as described above) is between 4 and 12 hours.

5, according to the medicinal unit dosage forms of arbitrary claim in the claim 1 to 4, it contains 10 to 500mg morphines (by morphine sulfate).

6, according to the medicinal unit dosage forms of above-mentioned arbitrary claim, its release in vitro is characterized as: the active component of said preparation release 5-30% in 2 hours after on-test, after on-test, discharged 15-50% in 4 hours, after on-test, discharged 20-60% in 6 hours, after on-test, discharged 35-75% in 12 hours, after on-test, discharged 45-100% in 18 hours, and 24 hours release 55-100%(contain the aqueous buffer solution (pH6.5) of 0.5% tween in 37 ℃ mensuration in 100 rev/mins at 900ml with the Ph.Eur. Basket method that improves after on-test).

7,, comprise and contain the multiple particulate capsule of mainly forming by described active component and hydrophobicity controlled release material according to the medicinal unit dosage forms of above-mentioned arbitrary claim.

8, according to the medicinal unit dosage forms of claim 7, wherein, described multiple granule also contains the release components that accounts for its gross weight 0.01-20%, and this release components comprises meltable material of water solublity or the solvable or insoluble organic or inorganic material of graininess.

9, according to the medicinal unit dosage forms of claim 7 or 8, wherein, described multiple granule comprises active medicinal matter, and it is that described dosage form can contain conventional glue capsule excipient in 35-150 ℃ the substrate of hydrophobic meltable material that this material is stored in fusing point.

10, with the obtainable medicinal unit dosage forms of following method: will comprise and be stored in the multiple granule compression that fusing point is the active medicinal matter in 35-150 ℃ the hydrophobic meltable material substrate; This dosage form can contain conventional tabletting excipient.

11, according to the unit dosage forms of arbitrary claim in the claim 7 to 10, wherein, described multiple granule is the granule that obtains with the method that comprises the steps: to comprising granular medicament and granular fusing point is that 35-150 ℃ the hydrophobic meltable carrier or the mixture of diluent carry out the high speed machine processing, and the input energy is so that described carrier or diluent melt or soften and form the multiple granule of required size.

12, according to the described unit dosage forms of arbitrary claim in the claim 7 to 11, wherein, described multiple granule makes with following method: but in super mixer, handle the mixture of the release regulator that comprises described active component, hydrophobic meltable carrier or diluent and optional with a certain speed mechanical, and supply with enough energy so that described meltable material fusing or softening, formation contains the granule of described active component, tells the granule in the desired particle size range then.

13, according to the described unit dosage forms of arbitrary claim in the claim 7 to 12, wherein, described multiple granule contains release regulator, and it is a hydrophilic release modifier, perhaps water solublity or water-insoluble graininess organic or inorganic material.

14, contain the preparation method of the multiple granule of slow release of morphine or its pharmaceutically acceptable salt, it comprises:

(a) in super mixer, to containing graininess morphine or its pharmaceutically acceptable salt and graininess fusing point is but that the mixture of the release components of 35 to 150 ℃ hydrophobic meltable carrier or diluent and optional carries out mechanization with a certain speed and handles, and import energy, thereby form agglutinator so that described carrier or diluent melt or be softening; Described release components comprises the meltable material of water solublity, perhaps graininess solubility or insoluble organic or inorganic material;

(b) described agglutinator is pulverized to obtain controlled release granule; And can

(c) continue mechanical treatment, can add the described carrier and the diluent of low percentage amounts simultaneously again; And can

(d) repeating step (c) and possible step (b) 1 time or repeatedly.

15, according to the method for claim 14, wherein, during described mechanization is handled, to wherein using the microwave radiation heat supply.

16, according to the method for claim 15, wherein, only the part heat provides with microwave radiation.

17, according to the method for arbitrary claim in the claim 12 to 14, wherein, described hydrophobic meltable carrier or diluent are wax, for example are selected from hydrogenated vegetable oil, castor oil hydrogenated, Cera Flava, Brazil wax, microwax and glyceryl monostearate.

18, according to the method for arbitrary claim in the claim 14 to 17, meltable material of water solublity in the wherein said mixture that can randomly be included in the step (a) or diluent are that molecular weight is PEG or the poloxamer of 1000-20000.

19, according to the method for arbitrary claim in the claim 14 to 18, wherein, described meltable carrier or diluent are added during mechanical treatment step by step.

20, according to the unit dosage forms of arbitrary claim in the claim 7 to 13, wherein, described granule can obtain with the defined method of arbitrary claim in the claim 12 to 17.

21, the foregoing substantially Pharmaceutical composition described in claim 1 of reference example.

22, the preparation method of the foregoing substantially slow-releasing granules according to claim 14 of reference example.

23, the preparation method of the foregoing substantially unit dosage forms according to claim 7 or 10 of reference example.