CN1957909A - Methods of reducing alcohol-induced dose dumping for opioid sustained release oral dosage forms - Google Patents
Methods of reducing alcohol-induced dose dumping for opioid sustained release oral dosage forms Download PDFInfo
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- CN1957909A CN1957909A CN 200610143171 CN200610143171A CN1957909A CN 1957909 A CN1957909 A CN 1957909A CN 200610143171 CN200610143171 CN 200610143171 CN 200610143171 A CN200610143171 A CN 200610143171A CN 1957909 A CN1957909 A CN 1957909A
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Abstract
Disclosed are methods of sustained release administration of opioids, including but not limited to hydromorphone and oxycodone, that exhibit improved properties with respect to co-ingestion with aqueous alcohol.
Description
Technical field
The present invention relates to the method for opioid (including but not limited to hydromorphone and oxycodone) sustained release administration, it shows improved character with the alcohol-water solution administering drug combinations time.
Background technology
The dose dumping that alcohol induced opioid continues the liberation port oral dosage form discharges for serious problem of the patient Lai Shuoshi that takes this peroral dosage form.
Opioid continues to send opioid to the patient in period that the liberation port oral dosage form is designed in continuity.Continue the liberation port oral dosage form through potion opioid commonly used and replace multi-agent opioid instantaneous relase peroral dosage form.For example, the great demand that exists for once a day (qd) and every day twice (bid) to use the lasting liberation port oral dosage form of opioid alleviates patient's misery of all day.
Therefore, the amount of the contained opioid of this dosage form (opioid especially once a day continues the liberation port oral dosage form) is significantly higher than the amount that is comprised traditionally in instantaneous relase opioid peroral dosage form.Any situation that causes the dose dumping release of the lasting liberation port oral dosage form of this opioid can cause the opioid overdose, causes respiratory failure and even possibility death.
The inventor recognizes that a kind of mode that causes dose dumping to discharge (that is instantaneous relase) is the quickening that continues the delivery rate that liberation port oral dosage form and alcohol-water solution (especially ethanol water) administering drug combinations cause by opioid.Various alcohol can increase opioid and continue to discharge with undesirable two-forty the liberation port oral dosage form from opioid, even cause dose dumping release/instantaneous relase.
Therefore, hope can be developed opioid and be continued liberation port oral dosage form and correlation technique, and it does not have the problem that alcohol-induced dose dumping that prior art relates to discharges (especially alcohol induced dose dumping discharges).Even more wish those opioids to continue liberation port oral dosage form and correlation technique be every day with once or every day with lasting liberation port oral dosage form of twice opioid and correlation technique.
Summary of the invention
In one aspect, the present invention relates to a kind of method, it comprises: provide use the lasting release dosage structure of dose with the lasting liberation port oral dosage form of the hydromorphone that contains hydromorphone once every day with providing every day; Use hydromorphone once to continue liberation port oral dosage form and alcohol-water solution every day to patient's administering drug combinations; Use hydromorphone once to continue to discharge hydromorphone the liberation port oral dosage form from every day; Wherein, alcohol-water solution contains the alcohol that is equal to or greater than about 20% volume/volume concentration; And wherein, the maximum blood plasma hydromorphone of the average single agent concentration that is reached when continue liberation port oral dosage form and alcohol-water solution to patient's administering drug combinations with once hydromorphone every day coexists that continue liberation port oral dosage form discord alcohol-water solution administering drug combinations with once hydromorphone every day and ratio between the maximum blood plasma hydromorphone of the average single agent concentration that reached during separately to patient's administration is equal to or less than about 1.8: 1.
In yet another aspect, the present invention relates to a kind of method, it comprises: provide use the lasting release dosage structure of dose with the lasting liberation port oral dosage form of the hydromorphone that contains hydromorphone once every day with providing every day; Use hydromorphone once to continue liberation port oral dosage form and alcohol-water solution every day to patient's administering drug combinations; Use hydromorphone once to continue to discharge hydromorphone the liberation port oral dosage form from every day; Wherein, alcohol-water solution contains the alcohol that is equal to or greater than about 20% volume/volume concentration; And wherein, the maximum blood plasma hydromorphone of the single patient list agent concentration that is reached when continue liberation port oral dosage form and alcohol-water solution to patient's administering drug combinations with once hydromorphone every day coexists that continue liberation port oral dosage form discord alcohol-water solution administering drug combinations with once hydromorphone every day and ratio between the maximum blood plasma hydromorphone of the single patient list agent concentration that reached during separately to patient's administration is equal to or less than about 5: 1.
In yet another aspect, the present invention relates to a kind of method, it comprises: provide use the lasting release dosage structure of dose with the lasting liberation port oral dosage form of the hydromorphone that contains hydromorphone once every day with providing every day; Use hydromorphone once to continue liberation port oral dosage form and alcohol-water solution every day to patient's administering drug combinations; Use hydromorphone once to continue to discharge hydromorphone the liberation port oral dosage form from every day; Wherein, continue dosage that liberation port oral dosage form discharge the hydromorphone that be less than or equal to about 80 percentage by weights with once hydromorphone every day, and the dosage of described hydromorphone continues the liberation port oral dosage form from every day with once hydromorphone and records as follows: (a) utilize to contain the testing in vitro method of tested media and (b) in the initial back of testing in vitro method in about 2 hours; And wherein, the tested media aqueous solution of alcohol, described alcohol-water solution contains the alcohol that is equal to or greater than about 20% volume/volume concentration.
In yet another aspect, the present invention relates to a kind of method, it comprises: provide the hydromorphone that contains hydromorphone to continue liberation port oral dosage form and a kind of lasting release dosage structure; Continue liberation port oral dosage form and alcohol-water solution to patient's administering drug combinations hydromorphone; Continue to discharge hydromorphone the liberation port oral dosage form from hydromorphone; Wherein, alcohol-water solution contains the alcohol that is equal to or greater than about 20% volume/volume concentration; And wherein, coexist this dosage form discord alcohol-water solution administering drug combinations and ratio between the maximum blood plasma hydromorphone of the average single agent concentration that reached during separately to patient's administration is equal to or less than about 1.8: 1 in the maximum blood plasma hydromorphone of the average single agent concentration that this dosage form and alcohol-water solution are reached during to patient's administering drug combinations.
In yet another aspect, the present invention relates to a kind of method, it comprises: provide the hydromorphone that contains hydromorphone to continue liberation port oral dosage form and a kind of lasting release dosage structure; Continue liberation port oral dosage form and alcohol-water solution to patient's administering drug combinations hydromorphone; Continue to discharge hydromorphone the liberation port oral dosage form from hydromorphone; Wherein, alcohol-water solution contains the alcohol that is equal to or greater than about 20% volume/volume concentration; And wherein, coexist this dosage form discord alcohol-water solution administering drug combinations and ratio between the maximum blood plasma hydromorphone of the single patient list agent concentration that reached during separately to patient's administration is equal to or less than about 5: 1 in the maximum blood plasma hydromorphone of the single patient list agent concentration that this dosage form and alcohol-water solution are reached during to patient's administering drug combinations.
In yet another aspect, the present invention relates to a kind of method, it comprises: provide the hydromorphone that contains hydromorphone to continue liberation port oral dosage form and a kind of lasting release dosage structure; Continue liberation port oral dosage form and alcohol-water solution to patient's administering drug combinations hydromorphone; Continue to discharge hydromorphone the liberation port oral dosage form from hydromorphone; Wherein, hydromorphone continues the liberation port oral dosage form and discharges dosage less than the hydromorphone of about 80 percentage by weights, and the dosage of described hydromorphone records as follows: (a) utilize to contain the testing in vitro method of tested media and (b) in the initial back of testing in vitro method in about 2 hours; And wherein, the tested media aqueous solution of alcohol, described alcohol-water solution contains the alcohol that is equal to or greater than about 20% volume/volume concentration.
In one aspect, the present invention relates to a kind of method, it comprises: provide the usefulness every day opioid that contains opioid once to continue liberation port oral dosage form and a kind of lasting release dosage structure that usefulness dose every day can be provided; To patient's administering drug combinations usefulness every day opioid sustained release forms and alcohol-water solution once; Discharge opioid from every day with the opioid sustained release forms once; Wherein, alcohol-water solution contains the alcohol that is equal to or greater than about 20% volume/volume concentration; And wherein, the ratio that the maximum blood plasma opioid of the average single agent concentration that is reached during to patient's administering drug combinations with once opioid sustained release forms and alcohol-water solution in every day coexists between the maximum blood plasma opioid of the average single agent concentration that is reached during with once opioid sustained release forms discord alcohol-water solution administering drug combinations and separately to patient's administration every day is equal to or less than about 1.8: 1.
In yet another aspect, the present invention relates to a kind of method, it comprises: the usefulness every day opioid sustained release forms that contains opioid and a kind of lasting release dosage structure that usefulness dose every day can be provided once is provided; Use opioid once to continue liberation port oral dosage form and alcohol-water solution every day to patient's administering drug combinations; Discharge opioid from every day with the opioid sustained release forms once; Wherein, alcohol-water solution contains the alcohol that is equal to or greater than about 20% volume/volume concentration; And wherein, the ratio that the maximum blood plasma opioid of the single patient list agent concentration that is reached when continue liberation port oral dosage form and alcohol-water solution to patient's administering drug combinations with once opioid every day coexists between the maximum blood plasma opioid of the single patient list agent concentration that is reached during with once opioid sustained release forms discord alcohol-water solution administering drug combinations and separately to patient's administration every day is equal to or less than about 5: 1.
In yet another aspect, the present invention relates to a kind of method, it comprises: the usefulness every day opioid sustained release forms that contains opioid and a kind of lasting release dosage structure that usefulness dose every day can be provided once is provided; Use opioid once to continue liberation port oral dosage form and alcohol-water solution every day to patient's administering drug combinations; Discharge opioid from every day with the opioid sustained release forms once; Wherein, discharge the dosage of the opioid that be less than or equal to about 80 percentage by weights with once opioid sustained release forms every day, and the dosage of the described opioid that discharges with once opioid sustained release forms from every day records as follows: (a) utilize to contain the testing in vitro method of tested media and (b) in the initial back of testing in vitro method in about 2 hours; And wherein, the tested media aqueous solution of alcohol, described alcohol-water solution contains the alcohol that is equal to or greater than about 20% volume/volume concentration.
In yet another aspect, the present invention relates to a kind of method, it comprises: the opioid sustained release forms and a kind of lasting release dosage structure that contain opioid are provided; To patient's administering drug combinations opioid sustained release forms and alcohol-water solution; From the opioid sustained release forms, discharge opioid; Wherein, alcohol-water solution contains the alcohol that is equal to or greater than about 20% volume/volume concentration; And wherein, coexist dosage form discord alcohol-water solution administering drug combinations and ratio between the maximum blood plasma opioid of the average single agent concentration that reached during separately to patient's administration is equal to or less than about 1.8: 1 in the maximum blood plasma opioid of the average single agent concentration that dosage form and alcohol-water solution are reached during to patient's administering drug combinations.
In yet another aspect, the present invention relates to a kind of method, it comprises: the opioid sustained release forms and a kind of lasting release dosage structure that contain opioid are provided; To patient's administering drug combinations opioid sustained release forms and alcohol-water solution; From the opioid sustained release forms, discharge opioid; Wherein, alcohol-water solution contains the alcohol that is equal to or greater than about 20% volume/volume concentration; And wherein, coexist dosage form discord alcohol-water solution administering drug combinations and ratio between the maximum blood plasma opioid of the single patient list agent concentration that reached during separately to patient's administration is equal to or less than about 5: 1 in the maximum blood plasma opioid of the single patient list agent concentration that dosage form and alcohol-water solution are reached during to patient's administering drug combinations.
In yet another aspect, the present invention relates to a kind of method, it comprises: the opioid sustained release forms and a kind of lasting release dosage structure that contain opioid are provided; To patient's administering drug combinations opioid sustained release forms and alcohol-water solution; From the opioid sustained release forms, discharge opioid; Wherein, the opioid sustained release forms discharges the dosage less than the opioid of about 80 percentage by weights, and the dosage of the described opioid that discharges from the opioid sustained release forms records as follows: (a) utilize to contain the testing in vitro method of tested media and (b) in the initial back of testing in vitro method in about 2 hours; And wherein, the tested media aqueous solution of alcohol, described alcohol-water solution contains the alcohol that is equal to or greater than about 20% volume/volume concentration.
In yet another aspect, the present invention relates to a kind of method, it comprises: the usefulness every day hydromorphone sustained release forms that contains hydromorphone and a kind of lasting release dosage structure that usefulness dose every day can be provided once is provided; To patient's administering drug combinations usefulness every day hydromorphone sustained release forms and alcohol-water solution once; Discharge hydromorphone from every day with the hydromorphone sustained release forms once; Wherein, alcohol-water solution contains the alcohol that is equal to or greater than about 20% volume/volume concentration; And wherein, the ratio that coexists between the time median of single agent maximal plasma concentration of being reached during with once hydromorphone sustained release forms discord alcohol-water solution administering drug combinations and separately to patient's administration every day at the time median of single agent maximal plasma concentration that dosage form and alcohol-water solution are reached during to patient's administering drug combinations is about 0.5 to about 1.0.
In yet another aspect, the present invention relates to a kind of method, it comprises: the hydromorphone sustained release forms and a kind of lasting release dosage structure that contain hydromorphone are provided; To patient's administering drug combinations hydromorphone sustained release forms and alcohol-water solution; From the hydromorphone sustained release forms, discharge hydromorphone; Wherein, alcohol-water solution contains the alcohol that is equal to or greater than about 20% volume/volume concentration; And wherein, coexist that hydromorphone continues liberation port oral dosage form discord alcohol-water solution administering drug combinations and ratio between the time median of single agent maximal plasma concentration of being reached during separately to patient's administration is about 0.5 to about 1.0 at the time median of single agent maximal plasma concentration that dosage form and alcohol-water solution are reached during to patient's administering drug combinations.
In one aspect, the present invention relates to a kind of method, it comprises: the usefulness every day opioid sustained release forms that contains opioid and a kind of lasting release dosage structure that usefulness dose every day can be provided once is provided; To patient's administering drug combinations usefulness every day opioid sustained release forms and alcohol-water solution once; Discharge opioid from every day with the opioid sustained release forms once; Wherein, alcohol-water solution contains the alcohol that is equal to or greater than about 20% volume/volume concentration; And wherein, the ratio that coexists between the time median of single agent maximal plasma concentration of being reached during with once opioid sustained release forms discord alcohol-water solution administering drug combinations and separately to patient's administration every day at the time median of single agent maximal plasma concentration that dosage form and alcohol-water solution are reached during to patient's administering drug combinations is about 0.5 to about 1.0.
In yet another aspect, the present invention relates to a kind of method, it comprises: the opioid sustained release forms and a kind of lasting release dosage structure that contain opioid are provided; To patient's administering drug combinations opioid sustained release forms and alcohol-water solution; From the opioid sustained release forms, discharge opioid; Wherein, alcohol-water solution contains the alcohol that is equal to or greater than about 20% volume/volume concentration; And wherein, coexist opioid sustained release forms discord alcohol-water solution administering drug combinations and ratio between the time median of single agent maximal plasma concentration of being reached during separately to patient's administration is about 0.5 to about 1.0 at the time median of single agent maximal plasma concentration that dosage form and alcohol-water solution are reached during to patient's administering drug combinations.
Description of drawings
Fig. 1 has shown exemplary according to osmotic pumps dosage form of the present invention.
Fig. 2 has shown the example of sustained release forms of the present invention.
Fig. 3 has shown the dosage form that another is exemplary.
Fig. 4 has shown the dosage form that another is exemplary.
Fig. 5 A-5C has shown the dosage form that another is exemplary.
Fig. 6 has shown in ethanol water the external accumulative total release profiles according to the 16mg tablet of dihydromorphinone hydrochloride of the present invention.
Fig. 7 has shown in ethanol water the comparison according to the solubility curve between dihydromorphinone hydrochloride 16mg of the present invention and the PalladoneXL 32mg.
Fig. 8 has shown on average (and SD) hydromorphone plasma concentration curve.
Fig. 9 has shown on average (and SD) hydromorphone plasma concentration curve.
Figure 10 has shown single Cmax ratio: group 1 alcohol research and same dose research.
Figure 11 has shown single Cmax ratio: group 2 alcohol researchs and same dose research.
Figure 12 has shown that oxycodone hydrochloride is from there being or not having release the preparation of stearyl alcohol.
Figure 13 has shown that dihydromorphinone hydrochloride is from there being or not having release the preparation of stearyl alcohol.
Figure 14 has shown the effect of Eudragit RS PO to the oxycodone hydrochloride drug release.
Figure 15 has shown the effect of Eudragit RS PO to the dihydromorphinone hydrochloride drug release.
Figure 16 has shown the effect to the oxycodone hydrochloride release function of stearyl alcohol, Brazil wax and hydrogenation polyhydroxy 60 Oleum Ricini.
Figure 17 has shown the dissolution in vitro curve of OxyContin tablet.
1. described opioid continues the liberation port oral dosage form
After recognizing above-mentioned the problems of the prior art, the inventor has unexpectedly found the invention scheme, and it can provide the solution that discharges (especially alcohol induced dose dumping discharges) at alcohol-induced dose dumping.
In this discovery, to should be mentioned that and not recognize in the prior art and utilize method of the present invention and relevant sustained release forms to solve the problem that dose dumping that alcohol-induced (especially alcohol induced) cause discharges.Prevent that at it character of abusing from using to those similar dosage forms that disclose herein, and do not exist instruction or prompting to think that these structures can be used for solving the relevant problem of dose dumping release with alcohol-induced (especially alcohol induced) in the prior art.Disclosed a kind of cation exchange resin of meticulous granular size as, the disclosed patent application 2005163856 of the U.S. of Maloney etc., it is contained in the oxycodone dosage form, can improve the performance of dosage form vitro extraction, can be used by potential misuser.Maloney etc. does not instruct or points out this character to can be used for solving alcohol-water solution that the inventor has in mind and induce the problem that dose dumping discharges in the body of (especially ethanol water is induced).That instruction or prompting are provided by the inventor.
It is as follows that the present invention is not present in prior to other evidences in the technology of the present invention: other people dose dumping that in fact locks into alcohol-induced (especially alcohol induced) that exploitation continue to discharge opioid dosage form technology discharges.Release hydromorphone (Purdue Pharma LP), Kadian (Alpharma US Pharms) and Avinza (Ligand Pharmaceuticals) problem that the dose dumping that relates to alcohol-induced (especially alcohol induced) discharges that all is in the news after the sentence expires as, Palladone .Although be attended by the risk that the dose dumping of alcohol-induced (especially alcohol induced) discharges, these products fact proved that by commercialization problem that provides and solution are not included in the prior art of the present invention herein.
After recognizing problem and its solution, the inventor has investigated many embodiment of the present invention.In certain embodiments, may provide dosage form coatings to reduce or prevent that the inductive dose dumping of alcohol-water solution from discharging.In other embodiments, can select some hydrophobic and/or hydrophilic component to reduce or prevent that the inductive dose dumping of alcohol-water solution from discharging.In the dosage form coatings scheme of protectiveness, the coating of selection can be used for revising release time, as enteric coatings, perhaps can prevent swelling or dissolving in alcohol, as semipermeable membrane coating or some non-enteric coatings.
In selecting hydrophobic ingredient to reduce or preventing scheme that the inductive dose dumping of alcohol-water solution discharges, swell in the material of alcohol-water solution preferred water insoluble relatively and minimum level.As, optional hydrophobic polymer, it is insoluble to relatively also and swells in water minimum level, and demonstrates equivalent or swelling still less and/or dissolubility in alcohol-water solution.In comprising the scheme of non-polymeric hydrophobic ingredient, (include but not limited to wax or fatty acid alcohol), preferably those of dissolving/swellability still less in alcohol-water solution than in water as the stearyl alcohol.Selecting hydrophilic component to reduce or preventing in the scheme of the inductive dose dumping release of alcohol-water solution, preferably more insoluble the and less material that tends to swell in alcohol-water solution with respect to water.As, optional hydrophilic polymer, it demonstrates equivalent or still less swelling in alcohol-water solution and/or dissolubility with respect to water.In comprising the scheme of non-polymeric hydrophilic component, preferred those of dissolving/swellability still less in alcohol-water solution than in water.
Being used for the technology that the present invention realizes desired coating and hydrophobic and hydrophobic ingredient is to the material plastic film in the review and tests the swellability of these materials when alcohol-water solution exists.A large amount of triage techniqueses can be used for this film test, thereby a large amount of suitable materials is provided.Similar technology can be used for assessing the dissolubility that expectation is used for the material of the present invention's practice.The work embodiment that discovery is used for the material of the present invention's practice can find in this paper other parts.
Shown in the disclosed invention scheme of following examples (especially embodiment 5), may with the alcohol-water solution administering drug combinations time, control the amount that continues to discharge the liberation port oral dosage form opioid from opioid.In following proposal, alcohol-water solution (as ethanol water) does not cause opioid out of control, instantaneous relase from the dosage form scheme that the inventive method is put into practice.As, in embodiment 5, when with the stationary state drug treatment, observe the hydromorphone release rate and depend on the concentration of alcohol increase, cause the slight increase of Cmax and the minimizing of intermediate value Tmax (with respect to 0% alcoholic acid 6h, with alcohol then the Tmax minima be 4 hours, and with respect to 0% ethanol, use 40% Ethanol Treatment, observe in any individuality that Cmax is maximum to increase by 2.5 times)., can cause the serious dose dumping of potential critical defect to discharge not appearance.
In embodiment 5, at first time point of taking medicine back 2 hours, blood plasma opioid (being hydromorphone in this example) concentration approaches quantitation limit; Afterwards, in 4 kinds of processing modes of all medicine feeds and fixing group, plasma concentration slowly raises.The Tmax median was between 12 and 16 hours, and the Tmax scope is similar between each group processing mode.The controlled release character of these Notes of Key Data exemplary dosage form is also kept in the presence of ethanol, does not have " dose dumping release ".The maintenance of controlled release character is consistent with the present invention program's in vitro results, and it has disclosed in embodiment 1 and 2 and has continued to be exposed to ethanol and also do not demonstrate dose dumping under surpassing 24 hours and discharge.
These data of hydromorphone dosage form of the present invention are opposite with the hydromorphone conventional formulation institute results reported that is called Palladone (deriving from Purdue Pharma).For that product, can see in vivo with external all has a large amount of " dose dumping release ".External, shown in embodiment 2, about 90% medicine discharged in 1 hour in ethanol.In the individual subjects body, for 4%, 20% and 40% ethanol, with respect to 0% ethanol, the maximum haplotype data report that Cmax increases is respectively about 2.0,5.7 and 15.7, and for 4%, 20% and 40% ethanol, with respect to 0% ethanol, be respectively about 1.1,2.1 and 5.8 for the maximum haplotype data report of the increase of all experimenters' average value added Cmax.
The material that is used for the present invention's practice has description in content of the present invention, especially in embodiment 1-3 and 7-11.Many materials of the present invention that are used to put into practice are disclosed.That interesting is OxyContin , and the prolongation that can derive from Purdue Pharma LP discharges the oxycodone product, tests as embodiment 12, can demonstrate the slightest phenomenon that dose dumping discharges when having alcohol-water solution.As a part of the present invention, have been found that the excipient stearyl alcohol can cause OxyContin can resist alcohol-induced dose dumping to discharge.This discovery is the evidence of the beat all character of the present invention.OxyContin has used for many years, but the discovery of the character that its anti-alcohol-induced dose dumping discharges and this resistance potential mechanism has been described this discovery up to this paper and just known.Can find except comprising other preparation strategies of stearyl alcohol in this paper other parts, it can be used for open sustained release forms and correlation technique provides the repellence that the inductive dose dumping of alcohol-water solution is discharged.Some this class embodiment is shown in embodiment 7-11.
Now, below the present invention will be described in more detail.
II. definition
Except other explanation is arranged, all percentage ratios all are weight percentage.
All open source literatures of using are herein all included this paper reference in full, just look like that they repeated the same in this article.
The present invention can by with reference to provided herein with give a definition, accompanying drawing and exemplary contents carry out best understanding.
" administration " or " medication " meaning is to provide medicine to the patient with effective and efficient manner pharmaceutically.
" alcohol " refers to organic compound, and it has from 1 to about 5 carbon atoms, and wherein (OH) link to each other with carbon atom, described carbon atom also is connected with other hydrogen and/or carbon atom to hydroxyl successively.In preferred embodiments, alcohol comprises ethanol.
" apparent termination half-life " (t1/2) can be regarded as 0.693/k, and wherein " k " refers to apparent elimination factor constant, can estimate by the linear attenuation to the number conversion plasma concentration in stopping logarithm-linear elimination phase.
" alcohol-water solution " refers to moisture and pure compositions.In alcohol-water solution, have the alcohol of variable number.In the preferred alcohols aqueous solution, alcohol-water solution contains about 1 volume/volume percentage ratio (v/v%, it is pure volume/alcohol-water solution cumulative volume, represent with percentage ratio) to about 100v/v% alcohol, more preferably alcohol-water solution contains determining alcohol and is equal to or greater than about 20v/v%, more preferably alcohol-water solution contains determining alcohol and is equal to or greater than about 25v/v%, and more preferably alcohol-water solution contains determining alcohol and is equal to or greater than about 40v/v%.
" area under curve " or " AUC " is area measured under the plasma drug level curve.Usually, AUC be exclusively used in refer to plasma drug level curve institute elapsed time at interval and, begin-stop as AUC.Therefore AUC0-48 refers to the AUC of the plasma drug level curve that adds between 0 to 48 hour, and wherein 0 normally to patient's administration medicine or contain time of the dosage form of medicine.AUCt refers to 0 hour to finally detecting plasma drug level area under curve when obtaining concentration at time t, and it is calculated by trapezoidal rule.AUCinf refers to be extrapolated to the AUC value at unlimited place, its can be regarded as AUCt and be extrapolated to unlimited place area and, it can be calculated divided by k by time t (Ct) concentration.If (can't assess individual t1/2 value, the average t1/2 value that then will treat is used to calculate AUCinf.)。" average, single agent, plasma drug level area under curve AUCinf " refers to average A UCinf, it obtains according to several patients under different situations or to the same patient multiple dosing, can enough remove the administration influence, thereby after each patient's single-dose dosage form, make levels of drugs return level before administration.
" C " refers to the drug level in patient's blood plasma or the serum, represents with the quality of per unit volume usually, and every milliliter of nanogram is typically arranged.Usually, this concentration can refer to herein " drug plasma concentration ", " plasma drug level " or " plasma concentration ".The plasma drug level of any time is known as the C time after the administration, as C9h or C24h etc.Interpolation and the maximal plasma concentration that directly obtains from test data is known as C not behind the form of administration
Max, the mean plasma concentration that obtains in the pointed time is called as Cavg or C is average." average, single agent, maximal plasma concentration " refers to mean Cmax, it obtains according to several patients under different situations or to the same patient multiple dosing, can enough remove the administration influence, thereby after each patient's single-dose dosage form, make levels of drugs return level before administration." individual patients, single agent, maximal plasma concentration " refers to mean Cmax, and it can enough be removed the administration influence, thereby make levels of drugs return level before administration after each patient's single-dose dosage form according to obtaining at the single patient single-dose.
In embodiments, the inventive method comprises, from the opioid sustained release forms (preferred every day with once or every day with twice opioid sustained release forms) discharge opioid (such as, but not limited to hydromorphone and oxycodone), wherein, coexist opioid sustained release forms discord alcohol-water solution administering drug combinations and ratio between the maximum blood plasma opioid of the average single agent concentration that reached during separately to patient's administration is equal to or less than about 1.8: 1 in the maximum blood plasma opioid of the average single agent concentration that opioid sustained release forms and alcohol-water solution are reached during to patient's administering drug combinations, more preferably be equal to or less than about 1.6: 1, and even more preferably be equal to or less than about 1.4: 1.
In embodiments, the inventive method comprises, from the opioid sustained release forms, discharge opioid (such as, but not limited to hydromorphone and oxycodone), wherein, the opioid sustained release forms (preferred every day with once or every day with twice opioid sustained release forms) and the maximum blood plasma opioid of the single patient list agent concentration that reached during to patient's administering drug combinations of alcohol-water solution coexist opioid sustained release forms discord alcohol-water solution administering drug combinations and ratio between the single patient list agent maximum blood plasma opioid concentration that reached during separately to patient's administration is equal to or less than about 5: 1, preferably be equal to or less than about 4: 1, more preferably be equal to or less than about 3: 1.
" administration altogether ", " shared medicine " and " administering drug combinations " all point to patient's two or more materials of administration in finite time, preferably in 180 minutes, more preferably in 60 minutes, even more preferably in 45 minutes, more preferably in 30 minutes, and more preferably in 15 minutes.
" dosage form " refers to be in the suitable opioid to patient's administration in medium, carrier, media or the equipment." peroral dosage form " refers to be fit to the dosage form of oral administration.In embodiments, dosage form of the present invention can comprise the lasting release dosage structure that is used for continuing to discharge opioid, and the optional instantaneous relase composition that is used for the instantaneous relase opioid.In embodiments, dosage form of the present invention can comprise or not comprise, opioid antagonists is as naltrexone, naloxone or other conventional opioid antagonists.
" dosage " refers to pharmaceutical units.Usually, determine dosage with dosage form.Can be according to various therapeutic regimens to the patient with dosed administration.General therapeutic regimen comprises once a day (qd), every day twice (bid) and every day three times (tid).The opioid dosage that is used for the present invention practice is between about 0.001mg about 5000mg extremely, preferred about 0.01mg is to about 1000mg, more preferably from about 0.1mg is to about 750mg, preferred about 0.5mg is to about 500mg, more preferably from about 0.5mg is to about 250mg, more preferably from about 1mg is to about 100mg, and 1mg about 50mg extremely most preferably from about.
" instantaneous relase dosage form " pointed to be less than or equal to behind patient's form of administration and discharged the dosage form that is equal to or greater than about 75% medicine in about 45 minutes.
" once a day " (being qd) or " twice of every day " (being bid) refers to the medicine frequency according to the inventive method.As, medication once a day refers generally to per 24 hours innerlich anwendens once, as qd.
" opioid " refers to the reagent with the opioid receptors bind, and described opioid receptor is found in central nervous system and gastrointestinal tract in theory, and it is selected from papaverine and semi-synthetic or complete synthesis opioid.The example of papaverine comprises morphine, codeine and dimethyl morphine.The example of semi-synthetic opioid comprises diacetylmorphine (heroin), oxycodone, hydrocodone, paracodin, hydromorphone, oxymorphone and Ni Ke morphine.The example of complete synthesis opioid comprises methadone, hydrochloric acid levothyl ethyl ester (LAAM), meperidine(pethidine), ketobemidone, the third oxygen sweet smell, dextropropoxyphene, dextromoramide, bezitramide, pirinitramide, pentazocine and phenazocine.Other opioids are known to those skilled in the art.Preferred opioid comprises oral biocompatible opioid in the present invention's practice.Preferred opioid comprises morphine, hydromorphone, hydrocodone, oxymorphone and oxycodone.Opioid comprises the opioid of the present invention of pharmaceutically acceptable salt and free alkali or free acid form.In embodiments, opioid of the present invention continues the liberation port oral dosage form and comprises that about 0.01mg is to about 1000mg opioid, preferred about 0.1mg is to about 500mg opioid, and more preferably from about 0.25mg is to about 300mg opioid, and more preferably from about 1mg is to about 100mg opioid.It should be noted that the dissolubility of opioid of the present invention in water and/or alcohol-water solution has remarkable difference.In embodiments, the amount of the opioid in the sustained release forms and/or this opioid alcohol-water solution dissolubility can front or negative effect sustained release forms of the present invention and/or the dose dumping release performance of correlation technique in alcohol-water solution.As, in certain embodiments, insoluble opioid of a large amount of high alcohol-water solution and/or opioid form can increase the probability that the inductive dose dumping of alcohol-water solution discharges.On the contrary, in certain embodiments, deliquescent opioid of a large amount of high alcohol-water solution and/or opioid form can reduce the probability that the inductive dose dumping of alcohol-water solution discharges.
" oral lasting release dosage structure " refers to suitable structure to patient's oral administration, and it comprises one or more medicines, and wherein this structure can continue to discharge medicine." the oral lasting release dosage structure of permeability " refers to oral lasting release dosage structure, and wherein this structure continues to discharge medicine by the mechanism of permeating.
" patient " refers to the animal that the needs treatment is intervened, preferred mammal, more preferably people.
" pharmaceutically acceptable salt " refers to any salt, and its anion is not significantly made salifiable toxicity or pharmacological activity, and for example, they are medicine equivalents of medicine alkali.Suitable pharmaceutically acceptable salt comprises acid-addition salts, can generate described sour example hydrochloric acid, sulphuric acid, Fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid with suitable pharmaceutically acceptable acid reaction by medical compounds as it.
So representational pharmaceutically acceptable salt includes but not limited to following: acetate, benzene sulfonate, benzoate, bicarbonate, disulfate, biatrate, borate, bromide, the calcium edetate, camsilate, carbonate, chloride, Clavulanate, citrate, dihydrochloride, edetate, ethanedisulphonate, estolate, esilate, fumarate, gluceptate, gluconate, glutamate, Glu, ethylene glycol arsanilate (glycollylarsanilate), hexyl resorcin salt, Hai Baming salt (hydrabamine), hydrobromate, hydrochlorate, Hydroxynaphthoate, iodide, different thiosulfate, lactate, Lactobionate, laruate, malate, maleate, mandelate, mesylate, MB, methyl nitrate, Methylsulfate, mucate, naphthalene sulfonate, nitrate, N-methylglucosamine ammonium salt, oleate, embonate (embonate), palmitate, pantothenate, phosphate/diphosphate, Polygalacturonate, Salicylate, stearate, sulfate, basic acetate, succinate, tannate, tartrate, the teoclate, toluene fulfonate, triethyl group iodate thing and valerate.Representational pharmaceutically acceptable opioid salt includes but not limited to dihydromorphinone hydrochloride, oxycodone hydrochloride, morphine sulfate, hydrochloric acid oxymorphone and hydrogen tartrate hydrocodone.
" plasma drug level curve " or " drug plasma concentration curve " or " plasma concentration curve " or " curve of blood plasma " or " plasma concentration curve " refer to the curve that obtains by to plasma drug level or drug plasma concentration or plasma concentration and temporal mapping.Usually, be to patient's administration medicine or contain time of the dosage form of medicine at the point of 0 on the time range (usually on the x axle) traditionally.
" prolongation time interval " refers to be preferably greater than about 4 hours greater than about 2 hours consecutive hours interval, more preferably greater than about 8 hours, more preferably greater than about 10 hours, more preferably greater than about 14 hours, most preferably greater than about 14 hours and about at the most 24 hours.
" speed of release " or " release rate " refer to the amount of the medicine that time per unit discharges from dosage form, as the milligram number (mg/hr) of the medicine that per hour discharges.The drug release rate of dosage form can be the external drug release rate that records, promptly under appropriate condition and the amount of the medicine that discharges from dosage form of the time per unit that records with suitable tested media.
In preferred embodiments, can determine alleged release rate herein by dosage form being placed deionized water, quoit or the test of metal shaped as frame sample holder, described support is bathed indexer with USP VII type temperature and is linked to each other, and test is carried out in 37 ℃ water bath with thermostatic control.Collect the release rate solutions aliquot with pre-set interval, injection is fit to use the chromatographic system that uses with ultraviolet or refractive index detector to come the amount of the medicine of quantitative test interim release then.In other embodiments, other release rate tests common and external application also can be used for practice of the present invention, as using USP II type equipment, as DistekPremiere 5100.
In embodiments, utilize the testing in vitro method, opioid sustained release forms of the present invention from the opioid sustained release forms, discharge be less than or equal about 80 percentage by weights, preferably be less than or equal about 70 percentage by weights, more preferably less than or equal about 60 percentage by weights, more preferably less than or equal about 50 percentage by weights, more preferably less than or equal about 40 percentage by weights, most preferably be less than or equal the opioid dosage of about 25 percentage by weights.In preferred embodiments, the testing in vitro method, as testing in vitro method disclosed herein, or other conventional testing in vitro methods, having comprised test media, the opioid sustained release forms is placed in this media at test period.In embodiments, amount a period of time of the opioid that mensuration discharges from opioid sustained release forms of the present invention, preferred about 24 hours time after beginning testing in vitro method, more preferably about 12 hours time after beginning testing in vitro method, and more preferably about 2 hours time after beginning testing in vitro method.
In embodiments, test media comprises the alcohol-water solution that contains alcohol.In preferred embodiments, test media comprises and contains the alcohol-water solution that determining alcohol is equal to or greater than about 20% volume/volume (pure volume/test media cumulative volume), preferably be equal to or greater than about 25% volume/volume, more preferably be equal to or greater than about 30% volume/volume, more preferably be equal to or greater than about 35% volume/volume, most preferably be equal to or greater than about 40% volume/volume.
" continue discharge " or " release that continues " refers in long-time release continuously or discharges medicine or drug dose continuously.
" continue to discharge the dosage structure " and refer to one or more physical units, it provides and continues to discharge medicine or drug dose.
" sustained release forms " refers to a kind of dosage form type, and it provides and continues to discharge medicine or drug dose.
" meta, single agent, reach the time T max of maximal plasma concentration " refers to median, it obtains according to several patients or to the same patient multiple dosing, can enough remove the administration influence, thereby after each patient's single-dose, the dosage form that contains medicine to patient's administration through associating reaches the period of Cmax to this medicine, make levels of drugs return level before administration, it does not carry out interpolation and directly obtains from test data.In embodiments, coexist opioid sustained release forms discord alcohol-water solution administering drug combinations and ratio between the time median of single agent maximal plasma concentration of being reached during separately to patient's administration is about 0.5 to about 1.0 at the time median of single agent maximal plasma concentration that dosage form and alcohol-water solution are reached during to patient's administering drug combinations, preferred about 0.6 to about 1.0, more preferably from about 0.7 to about 1.0, and most preferably from about 0.75 to about 1.0.
" treatment effective dose " refers to the amount of medicine, and it can obtain biology or drug responses in researcher, tissue system that veterinary, pharmacist or other clinicists sought, animal or human, comprises the disease that improvement will be treated or the symptom of disease.
III. dosage form
In embodiments, be mixed with can be to the dosage form of patient's administration of needs for sustained release forms of the present invention.Sustained release forms and the Therapeutic Method that utilizes sustained release forms will be described now.Be appreciated that following sustained release forms only is exemplary.
Various sustained release formses are suitable for the present invention.In certain embodiments, dosage form is an oral administration, and its size and shape are as the tablet or the capsule of routine, and peroral dosage form can be made according to one of various distinct methods.As Pharmaceutical Sciences, Remington, the 18th edition, pp.1676-1686 (1990), Mack publishing company; The Pharmaceutical and Clinical Pharmacokinetics, the 3rd edition, pp.1-28 (1984), Lea and Febreger, Philadelphia is described, as, dosage form can be prepared into dispersion, as storing body or mould bed body, dissolution system, as capsule dissolves body (comprise as, " pill after a little while " and granule) and mould bed dissolve body, and unite diffusion/dissolve body and ion exchange resin body.
Osmotic dosage form general using osmotic pressure produces driving force, if exist, does not allow medicine or the dispersive semipermeable membrane of penetrating agent by allowing fluid freely to disperse, and liquid is sucked the cell that forms (to small part).The remarkable advantage of osmosis system is not rely on the pH operation also thereby in for a long time to continue release with the speed of permeating decision, even dosage form is transferred to the difference microenvironment that gastrointestinal tract will be faced remarkable different pH value.The summary of this class dosage form can be at Santus and Baker, and " Osmotic drug delivery:a review of the patentliterature " finds among Journal of Controlled Release 35 (1995) 1-21, and it includes this paper reference in.U.S. Patent No. 3845770,3916899,3995631,4008719,4111202,4160020,4327725,4578075,4681583,5019397 and 5156850 has disclosed the permeable mass that is used for continuing to distribute activating agent.
As described in U.S. Patent No. 5633011,5190765,5252338,5620705,4931285,5006346,5024842 and 5160743, infiltration sustained release forms Chinese medicine compositions is sent from little outlet in order to serosity, suspension or solution by the work of extension layer, and it includes this paper reference in.Exemplary systems comprises extendible promoting layer and by the medicine layer of semipermeable membrane coating.In some cases, medicine layer has internal layer and delays pharmaceutical composition and be discharged in the environment for use or formation and the bonded annealing coating of semipermeable membrane.In embodiments, for the infiltration sustained release forms, available enteric coating prevents that further dose dumping from discharging, preferred a kind of alcohol-water solution and swollen enteric coating under alcohol-water solution and intestinal pH not of being insoluble to.Be the protection semipermeable membrane, with hydrophilic film (as polyvinyl alcohol) or hydrophobic material coating semipermeable membrane.If this layer makes less ethanol contact semipermeable membrane, then can avoid or minimize the swelling of semipermeable membrane.
Fig. 1 has shown exemplary dosage form, is called as basic osmotic pumps dosage form in the prior art.Dosage form 20 shown in cross section, is also referred to as basic osmotic pumps (EOP), comprises the semipermeable membrane 22 that centers on the inner cell 24 of coating.Inner cell comprises the single component layer that is called as medicine layer 26 herein, comprises the material of the present invention 28 with the mixed with excipients of selecting.Excipient is suitable for providing a kind of osmotically active gradient, and the liquid that absorbs external environment also forms the compound formulation that can send by film 22 and comes imbitition.Excipient can comprise the suitable suspending agent of also being called pharmaceutical carrier 30 herein, binding agent 32, lubricant 34 and be known as the osmotically active agent of penetrating agent 36.The exemplary materials section that is used for these compositions can find in teachings herein.
The semipermeable membrane 22 of osmotic dosage form is permeable for outside liquid, this liquid such as water and biofluid, but be impermeable to the composition in the inner cell substantially.At the dosage form duration of existence, to be used for film forming material be not erodible basically and be insoluble to biological fluid substantially.The representational polymer that is used to form semipermeable membrane comprises homopolymer and copolymer, as cellulose esters, cellulose ether and cellulose esters-ether.Flux-regulating agent can mix to come the film forming permeability for liquids of shape with filmogen.As, the reagent that liquid (as water) is produced remarkable permeability and increases is hydrophilic usually substantially, and the remarkable permeability of water generates is reduced those be hydrophobic usually substantially.Exemplary flux-regulating agent comprises the polyester of polyhydroxy-alcohol, poly-alkane glycol, polyolefin diols (polyalkylenediols), alkane glycol etc.
In the operation, owing to film 22 osmotic gradients of striding that exist the osmotically active agent to cause cause intestinal juice to see through film, medicine layer expand molten and in inner cell, form the compound formulation that can send (as, solution, suspension, serosity or other fluid compositions).The preparation that the present invention can send discharges from exporting 38, and liquid continues to enter inner cell.Even pharmaceutical preparation discharges from dosage form, fluid continues the cell that absorbs, thereby drives the release that continues.In this mode, material of the present invention discharges for a long time with lasting and successive mode.
Fig. 2 has shown the embodiment of sustained release forms of the present invention.The type dosage form has description in U.S. Patent No. 4612008,5082668 and 5091190, and further as described below.
Fig. 2 has shown the embodiment of a class sustained release forms (promptly permeating sustained release forms).First medicine layer 30 comprises the opioid of osmotically active composition and ratio second medicine layer 40 less amount.Osmotically active composition in the first ingredient layer comprises penetrating agent (as salt) and one or more osmopolymer, it has relatively little molecular weight, demonstrate bloated dissolubility, similar to medicine layer 40, suck liquid and make by exporting 60 releases that these osmopolymer occur.Other excipient also can be included in first medicine layer 30 as binding agent, lubricant, antioxidant and coloring agent.
Other carriers that can be integrated into medicine layer 40 and/or medicine layer 30 comprise carbohydrate, and it demonstrates enough osmotically actives, can use separately or with other penetrating agent.This carbohydrate comprises monosaccharide, disaccharide and polysaccharide, and representational example comprises maltodextrin (i.e. the glucose polymer that produces by hydrolysed corn starch) and contains the sugar of lactose, glucose, Raffinose, sucrose, mannitol, sorbitol etc.Preferred maltodextrin, it has 20 or glucose equivalents (DE) still less, and preferred DE is between about 4 to about 20, and is generally 9-20.The maltodextrin that discovery has 9-12 DE is effective.
According to pattern of the present invention and mode, medicine layer 40 can be made by being ground into granule, pulverizes to produce to be applicable to the medicine size of making medicine layer and the polymer sizes of following, typically as the nuclear core that contains chemical compound.Produce that particulate mode comprises pelletize, spray drying, sieves, lyophilizing, crushing, grinding, jetly mill, micronization and cutting, to produce desired micron particles size.
Carry out this process by the equipment that reduces size, grind mill, centrifugal grinding mill, coarse grain breaker and meticulous breaker as miniature grinding mill, fluid energy mill mill, rotation mill, Chui mill, friction mill, chaser mill (chasermill), ball milling, the ball milling that shakes, collision.Granular size can be next definite by screening, and comprises grizzly screening, plate screening, concussion screening, rotation screening, shakes screening, vibration screening and reciprocal the screening.The process and the equipment of preparation medicine and carrier granular are disclosed in Pharmaceutical Sciences, Reminton, the 17th edition, pp.1585-1594 (1985); Chemical Engineers Handbook, Perry, the 6th edition, pp.21-13 to 21-19 (1984); Journal of Pharmaceutical Sciences, Parrot, the 61st volume, 6 phases, pp.813-829 (1974); With Chemical Engineer, Hixon, pp.94-103 (1990).
Osmotically active composition in the first composition medicine layer comprises penetrating agent and one or more osmopolymer usually, it has relatively little molecular weight, demonstrate bloated dissolubility, similar to medicine layer 40, suck liquid and make by exporting 60 releases that these osmopolymer occur.
Opioid concentration rate between first medicine layer and second medicine layer has changed the release rate curve.The release rate curve is calculated as maximum release rate and the release rate that obtains at initial back very first time point (as at 6 hours) poor, divided by the average release rate between two data points.
Disintegrating agent is selected from starch, clay, cellulose, alginic acid and glue and crosslinked starch, cellulose and polymer.Representational disintegrating agent comprises corn starch, potato starch, croscarmellose (croscarmelose), crospolyvinylpyrrolidone (crospovidone), Explotab, VeegumHV, methylcellulose, agar, bentonite, carboxymethyl cellulose, alginic acid, guar gum etc.
The film 20 that forms is permeable mistake for external fluid (as water and biofluid), and is impermeable mistake for paliperidone, penetrating agent, osmopolymer etc.So, it is semi permeable, and in the dosage form duration, the semi-transparent compositions of selectivity that is used for film forming 20 is not corrodible and insoluble at biofluid substantially substantially.
The polymer of representational formation film 20 comprises semi-transparent homopolymer, semi-transparent copolymer etc.In previous preferred scheme, compositions can comprise cellulose esters, cellulose ether and cellulose esters-ether.Cellulosic polymer is for its AGU form, has usually greater than 03 substitution value at the most " D.S. ".Substitution value refers to the average hydroxyl number in original AGU, and it can be replaced by substituent group, or changes into other groups.AGU can partly or entirely replace with following group: acyl group, alkanoyl, enoyl-, aroyl, alkyl, alkoxyl, halogen, carbon alkyl, alkyl carbamate, alkyl carbonate, alkyl sulfonic ester, alkyl amino sulphonic acid ester, semi-transparent polymer formation group etc.Semi-transparent compositions generally includes the member who is selected from the following group: acylated cellulose, two acylated celluloses, three acylated celluloses, Triafol T, cellulose acetate, cellulose diacetate, Triafol T, list-, two-and three-cellulose alkane esters, list-, two-, three-alkene ester and single-, two-, three-aroyl ester etc.
The polymer of example comprise as, have 1.8 to 2.3D.S. and contain the cellulose acetate of 32 to 39.9% acetyl content; Have 1 to 2D.S. and contain the cellulose diacetate of 21 to 35% acetyl content; Have 2 to 3D.S. and contain Triafol T of 34 to 44.8% acetyl group etc.Cellulosic polymer comprises the cellulose propionate that has 1.8D.S. and contain 38.5% propiono content more specifically; Contain cellulose acetate propionate 1.5 to 7% acetyl group and that contain 39 to 42% acetyl group; Contain 2.5 to 3% acetyl group, on average contain cellulose acetate propionate 39.2 to 45% propionos and that contain 2.8 to 5.4% hydroxyls; Have 1.8D.S., contain acetylbutyrylcellulose 13 to 15% acetyl group and that contain 34 to 39% bytyries; Contain 2 to 29% acetyl group, contain acetylbutyrylcellulose 17 to 53% bytyries and that contain 0.5 to 4.7% hydroxyl; Have 2.6 to 3D.S. three acyl group celluloses, draw agate acid (trilamate) cellulose, three Palmic acid celluloses, three sad celluloses and three cellulose propionates as three cellulose valerates, three; Has 2.2 to 2.6D.S. cellulose diester, as disuccinic acid cellulose, two Palmic acid celluloses, two sad celluloses and two carpylate celluloses etc.; Blended cellulose esters is as acetic acid cellulose valerate, cellulose acetate succinate, propanoic acid succinic acid cellulose, sad cellulose acetate, Palmic acid cellulose valerate, acetic acid enanthic acid cellulose etc.Semi-transparent polymer is open in U.S. Patent No. 4077407, and they can pass through as Interscience Publishers, Inc, the Encyclopedia of Polymer Science andTechnology that publish in New York, the 3rd volume, the 325-354 page or leaf, the method described in 1964 is synthesized.
Other semi-transparent polymer that forms semipermeable membrane can comprise as, acetaldehyde dimethyl cellulose acetate; The ethyl carbamic acid cellulose acetate; The methyl carbamic acid cellulose acetate; Diformazan ammonia cellulose acetate; Semi-transparent polyamide; Semi-transparent polyurethane; Semi-transparent sulfonated polystyrene; As U.S. Patent No. 3173876,3276586,3541005,3541006 and 3546142 disclosed co-precipitation polyanions and the semi-transparent polymer of the formed crosslinked selectivity of polycation; As U.S. Patent No. 3133132 disclosed semi-transparent polymer; Semi-transparent polystyrene derivative; Semi-transparent poly-(Sodium styrene sulfonate); Semi-transparent poly-(vinyl benzyl trimethyl ammonium chloride); Semi-transparent polymer, it demonstrates the fluid permeability of 10-5 to 10-2 (cc.Mil/cm hr.atm), and its each atmospheric pressure with the difference of hydrostatics of passing semipermeable membrane or osmotic pressure is represented.Polymer is known in following document: U.S. Patent No. 3845770,3916899 and 4160020; And CRCPress, Cleveland.Ohio publishes, Scott, J.R and Roff, the Handbook of CommonPolymers of W.J.1971.
Film 20 also can contain flux-regulating agent.Flux-regulating agent is the chemical compound that adds, the flow that it helps the regulated fluid permeability or passes film 20.Flux-regulating agent is the flux enhancement agent or reduces agent.But this reagent of preliminary election is to increase or to reduce fluid flow.It is hydrophilic usually substantially that convection cell (as water) generation significantly increases infiltrative reagent, and the infiltrative reagent of reduction is hydrophobic substantially and convection cell (as water) produces significantly.The amount of including the regulator in the film 20 of this paper in is usually from about 0.01% to 20% weight or more.The flux-regulating agent that increases flow in one embodiment comprises as, polyester of polyhydric alcohol, poly-alkane glycol, polyolefin diols, alkane glycol etc.Typical flux enhancement agent comprises Liquid Macrogol, 400,600,1500,4000,6000, poly-(ethylene glycol-be total to-ethylene glycol) etc.; Low molecular weight diols is as polypropylene glycol, polytetramethylene glycol and poly-pentanediol; Poly-alkane glycol is as poly-(1, ammediol), poly-(1, the 4-butanediol), poly-(1, the 6-hexanediol) etc.; Aliphatic diol, as 1,3 butylene glycol, 1,4-pentamethylene glycol, 1,4-hexamethylene glycol etc.; The alkene triol, as glycerol, 1,2,3-butantriol, 1,2,4-hexanetriol, 1,3,6-hexanetriol etc.; Ester is as ethylene glycol bisthioglycolate propyl ester, glycol butyl, butanediol dipropyl, acetic acid glycerine ester etc.Representational flow depressant comprise as, phthalic acid ester, it replaces with alkyl or alkoxyl or with alkyl and alkoxyl, as diethyl phthalate, dimethoxy-ethyl phthalic acid ester, dimethyl phthalic acid ester and [two (2-ethylhexyl) phthalic acid ester], aryl phthalic acid ester, as the triphenyl phthalic acid ester, and butyl benzyl phthalic ester; Insoluble salt is as calcium sulfate, barium sulfate, calcium phosphate etc.; Insoluble oxide is as titanium oxide; The polymer of form such as powdery, graininess is as polystyrene, poly methyl methacrylate, Merlon and polysulfones; Ester is as the citrate with the chain alkyl esterification; Inertia and fluid-tight substantially filler; With based on compatible resin of cellulose film formation material etc.
Other material that can be used for film forming 20 is used to make wall to have flexible and prolongation property, and be used to prepare the non-friable body of non-film and provide and pull intensity, it comprise as, phthalate plasticizers is as straight chain phthalic acid ester, the two-different nonyl phthalic acid ester of dibenzyl phthalic acid ester, dihexyl phthalic acid ester, fourth octyl group phthalic acid ester, 6 to 11 carbon, two-isodecyl phthalic acid ester etc.Plasticizer comprises non-phthalic acid ester, as glyceryl triacetate, dioctyl azelate, epoxidation ready denier oil acid ester, tri trimellitate isooctyl acrylate, the different nonyl ester of tri trimellitate, sucrose isobutyl acetate, epoxy soybean wet goods.The amount of including plasticizer in the film of this paper in is about 0.01% to 20% weight or more.
As shown in Figure 2, promoting layer 50 comprises extendible layer, and itself and second medicine layer 40 make contact to layered arrangement.Promoting layer 50 comprises polymer, and it absorbs water or biofluid and expand and passes the device outlet to promote pharmaceutical composition.
In an instantiation, extendible layer comprises by the activated compositions of water, and it expands in the presence of water, as in intestinal juice.Usually, it contains the penetrative composition that permeates solute, demonstrates osmotic pressure gradient along semipermeable membrane, resists the outside liquid that exists in the used environment.In another instantiation, comprise hydrogel by the activated layer of water, it is drawn fluid and/or absorb by outer semipermeable membrane and enters in the layer.Semipermeable membrane is nontoxic.It keeps its physics and chemistry integrity in operation and does not interact with extendible layer substantially.
In a preferred instantiation, extendible layer comprises the water active layer that contains hydrophilic polymer, is also referred to as osmopolymer.Osmopolymer shows absorption of fluids character.Osmopolymer is expandable, hydrophilic polymer, and this osmopolymer and water and biological aqueous solution interact, and expands or expands poised state to.Osmopolymer have the ability to demonstrate in water and biofluid expand and in polymer architecture, keep considerable part absorption liquid.Osmopolymers swell or expand very high degree to demonstrates the increase of 2 to 50 times of volumes with layer.Osmopolymer is a non-crosslinked or crosslinked.In an instantiation, lightly crosslinked behind inflatable, the hydrophilic swelling polymer, this is crosslinked to form by covalency or ionic bond or remaining crystalline region.Osmopolymer can be from plant, animal or synthetic.
Osmopolymer is a hydrophilic polymer.The hydrophilic polymer that is fit to this purpose comprises poly-(hydroxyl-alkylmethacrylate) with 30000 to 5000000 molecular weight; Poly-(vinylpyrrolidone) with 10000 to 360000 molecular weight; Anion and cationic water gel; Poly-electrolysis complex; Poly-(vinyl alcohol), its have low acetic acid residue, with Biformyl, formaldehyde or glutaraldehyde cross-linking, and have 200 to 30000 the degree of polymerization; Methylcellulose, crosslinked agar and the mixture of carboxymethyl cellulose; The mixture of hydroxypropyl emthylcellulose and sodium carboxymethyl cellulose, the mixture of Cellulose ethyl hydroxypropyl ether and sodium carboxymethyl cellulose, the mixture of sodium carboxymethyl cellulose and methylcellulose, sodium carboxymethyl cellulose; Carboxymethyl cellulose potassium; Expansible copolymer in water-fast, the water, it is formed by the maleic anhydride copolymers of segmentation and the dispersion of styrene, ethylene, propylene, butylene or isobutene., and every mole of maleic anhydride of its each copolymer is crosslinked to have 0.001 to about 0.5 mole of saturated cross-linking agent; Water expandable polymer N-vinyl lactam; Poly(ethylene oxide)-polyoxypropylene glue; Tragon; Polyacrylic acid glue; Polyester glue; Polyuria glue; Polyethers glue; Polyamide glue; Poly-cellulose gum; Poly-natural gum; The initial hydrogel of doing, its absorption and absorption water, it sees through vitreous hydrogel and reduces glass temperature; Or the like.
The representative of other osmopolymer is the polymer that forms hydrogel, as Carbopol
TMAcid carboxyl polymer with the crosslinked acrylate copolymer of polyene propyl group sucrose, is also referred to as the carboxylic polymethylene, and the carboxy vinyl polymer with 250000 to 4000000 molecular weight; Cyanamer
TMPolyacrylamide; Crosslinked watery distension dissolubility indenes maleic anhydride polymer; Good-rite with 80000 to 200000 molecular weight
TMPolyacrylic acid; Have 100000 to 5000000 molecular weight and higher Polyox
TMPolyethylene oxide polymer; Starch graft copolymer; Aqua-Keeps
TMThe acrylate polymer polysaccharide, it contains condensation sucrose unit, as the crosslinked poly-gluran of diester; Or the like.The polymer of the formation hydrogel of representative is known in following prior art: U.S. Patent No. 3865108, No.4002173, No.4207893; With Chemical RubberCo., Cleveland, Scott that Ohio publishes and the Handbook of Common Polymers of Roff.The amount of the osmopolymer of moisture active layer is about 5% to 100%.
Extendible layer in other goods can comprise effective infiltration chemical compound, and it comprises inorganic or organic compound, demonstrates the osmotic pressure gradient along semipermeable membrane, can anti-external fluid.Effectively the infiltration chemical compound as osmopolymer, sucks osmosis system with fluid, thereby makes available fluid to the pusher inwall, and promptly in some instantiations, barrier layer and/or film soft or hard capsule promote activating agent from dosage form.Effectively the infiltration chemical compound is also referred to as effective infiltration solute, and also is penetrating agent.Useful effective infiltration solute comprises magnesium sulfate, magnesium chloride, potassium sulfate, sodium sulfate, lithium sulfate, potassium phosphate, mannitol, carbamide, inose, Magnesium succinate, tartaric acid, carbohydrate, as Raffinose, sucrose, glucose, lactose, sorbitol and composition thereof.The amount of penetrating agent is about 5% to 100% of a layer weight.Extendible layer is optional to comprise osmopolymer and penetrating agent, and the total amount of osmopolymer and penetrating agent equals 100%.Effectively the infiltration solute is existing known, as described in the U.S. Patent No. 4783337.
But protectiveness internal layer, inwall 90 permeate fluid make it to enter the cell that film 20 limits.Wall 90 provides lubricating function, is beneficial to first medicine layer 30, second medicine layer 40 and promoting layer 50 moving to outlet 60.Wall 90 can be formed by water wetted material and excipient.Wall 90 promotes pharmaceutical composition to discharge from cell and when sending end, when especially during dispersion dispersive serosity, suspending agent and solvent are very sticking, reduces the amount that is retained in the left drug compositions in the cell.Having water-repelling agent to there is no in the dosage form of inwall, finish send after, observed the medicine of abundant residues and stayed in the device.In some cases, after release rate has been tested 24 hours, 20% or bigger amount stay in the dosage form.Especially under the high situation of reactive compound cost, this improvement brings the advantage economically of essence, because it needn't load high amount of drug to guarantee required minimum medication amount of sending at medicine layer.Inner membrance 90 can form the outer coating of compression core core.
Most preferably (it prepares in organic solvent the mixture of hydroxy propyl cellulose and polyvidone, especially organic polar solvent, if any the lower alcohol of 1-8 carbon atom, preferred alcohol), hydroxy ethyl cellulose and the mixture (it prepares in aqueous solution) of HYDROXY PROPYL METHYLCELLULOSE and the mixture (it prepares in aqueous solution) of hydroxy ethyl cellulose and Polyethylene Glycol.Most preferably, wall 90 is included in the hydroxy propyl cellulose for preparing in the ethanol and the mixture of polyvidone.
Usually, the thickness of the weight that is used in the wall 90 on the compression core core and wall 90 and the dosage form Chinese medicine that remains in the release rate test as described herein are relevant.As in production operation, the weight of the wall 90 that the thickness of wall 90 is added in operating by the control coating is controlled.
When wall 90 forms the sublayer, promptly coating is comprising that wall 90 can be packed in the irregular surface that forms on the nuclear core by the tabletting process on one of first medicine layer, second medicine layer and promoting layer or the whole compositions in blocks.During dispersion medicine, the smooth outer surface that obtains makes between the compositions nuclear core of coating and the semipermeable membrane and slides easily, makes when finishing medication the pharmaceutical composition of residual lesser amt in the device.When wall 90 is formed material and is made by glue, in applied environment, form glue or glue sample internal layer easily with contacting of water, its viscosity can promote and reinforcing membrane 20 and medicine layer 30 and medicine layer 40 between sliding.
Except outlet, pan coating can be advantageously used in the dosage form that provides complete.In the pan coating system, also can be by the suitable film compositions being sprayed on continuously the containing on medicine layer, optional barrier layer and promoting layer three layers or the multilamellar nuclear core of compression, then in rotary pot, rotate, come according to circumstances to deposit the wall that is used for wall or film thus and form compositions.Because it can use on commercial size, so can use the pan coating device.Available other technologies are come the nuclear core of coating compression.In case coating is good, desciccator diaphragm in forced air oven or in the wet stove of temperature control is removed the production solvent in the dosage form.Usually wait according to available equipment, ambient conditions, solvent, coating thing, coating thickness and select drying condition.
Also available other packaging techniques.As, utilize the air suspension process technology to form the film or the wall of dosage form.This process is included in to have hanged in the air-flow and stirred compression core core and semipermeable membrane and forms compositions, is coated onto on the nuclear core up to film.The air suspension process is suitable for the independent film that forms dosage form.The air suspension process is in U.S. Patent No. 2799241; J.Am.Pharm.Assoc., the 48th volume, pp.451-459 (1959); And, the same, the 49th volume, pp.82-84 has description in (1960).Also available Wurster air suspension coating device comes coated dosage form, as utilizes chloroform methanol to prepare film formation material as cosolvent.Available Aeromatic air suspension coating device uses cosolvent.
In instantiation, as shown in Figure 2, sustained release forms of the present invention has at least one outlet 60.Outlet 60 operates the unified medicine that discharges from dosage form with the compression core core.During the preparation dosage form or in the applicating fluid environment, can provide outlet during by the dosage form delivering drugs.
Bore one or more outlets in that the drug form layer is terminal, but and the optional water soluble skin, its pigmentable
(as, the Opadry dyed layer) or clarify (as Opadry Clear
), its coating on dosage form so that the molding dosage form to be provided.
Be selected from by cracking that following material forms an outlet or a plurality of outlet provides the unified hole-outlet that discharges yardstick: sorbitol, lactose, fructose, glucose, mannose, galactose, talose, sodium chloride, potassium chloride, sodium citrate and mannitol.
Be unified metering release medicine from dosage form, outlet can be an Any shape, as circle, triangle, square, ellipse etc.Sustained release forms can be built with one or more outlets in the isolating environment in the space of sustained release forms or on one or more surface.
Bore, comprise that machinery and laser bore, and bore semipermeable membrane and form outlet.This outlet and the equipment that is used to form this outlet have open in following document: the U.S. Patent No. 4088864 of the U.S. Patent No. 3916899 of Theeuwes and Higuchi and Theeuwes etc.Two isodiametric outlets of preferred at present use.In preferred instantiation,, then export 60 and penetrate sublayer 90 to medicine layer 30 as existing.
By the dosage form of standard method preparation according to example shown in Figure 1.As, prepare dosage form by the wet granulation technology.In the wet granulation technology,, be used as the pelletize fluid with organic solvent (as the degeneration dehydrated alcohol) hybrid medicine and carrier.Residual components dissolves in the pelletize fluid, and as above-mentioned solvent, the wet mixture of this latter's preparation slowly is added in the medicine, continues to mix in blender.Add the pelletize fluid up to producing wet mixture, then this wet mixture is added on the furnace tray by predetermined sieve.At 24 ℃ to 35 ℃ drying composites 18 to 24 hours in the forced air stove.The dried granules of sieving then.
Then, magnesium stearate or other examples of suitable lubricants are added in the drug particles, and granule put into jar mill and mix 10 minutes on jar mill.As in Manesty squeezer or Korsch LCT squeezer, compositions is pressed into layer.For three layers of nuclear core; the granule of drug layer composition and promoting layer compositions or powder are added in the mould of suitable size in proper order; to each two-layer intermediate compression step of carrying out, then after being added mould, last one deck carries out last compression step, to form three layers of nuclear core.Intermediate compression is carried out under about 50-100 newton's power usually.Terminal stage compression is carried out under 3500 newton or bigger power usually, is generally 3500-5000 newton.The nuclear core of compression is added in the drying pressure coating machine (coater press), as Kilian drying pressure coating machine, then with above-mentioned membrane material coating.
In another instantiation, hybrid medicine and contain other compositions of medicine layer, and be pressed in the solid layer.The size that this layer has is corresponding to the layer internal area size of occupying in the dosage form, and this size also comprises the size corresponding to promoting layer, arranges with the contact that forms wherein.Medicine and other compositions also useable solvents mix, and are mixed in solid or the semi-solid form by conventional method, as by ball milling, calendering, stirring or spin finishing, are pressed into the shape of preliminary election then.If comprise, then then the osmopolymer layer is contacted with medicine layer in a similar manner.The stratification of pharmaceutical preparation and osmopolymer layer can be finished by the two-layer compact technique of routine.Similar procedure can be then used in three layers of nuclear of preparation core.The compression core core can be with above-mentioned wall material and semipermeable membrane material coating then.
Available other manufacture process is included in mixes every layer powdery composition in the fluidized bed prilling device.Do mixed powdery composition in nodulizer after, pelletize fluid (as poly-(vinylpyrrolidone) in water) is sprayed on the powder.The powder of dry coationg in nodulizer then.Add the pelletize fluid simultaneously, the composition that this method appears at wherein all forms granule.Behind the dried particles, use blender,, lubricant (as stearic acid or magnesium stearate) is sneaked into granule as V-blender or portable blender.Press granule then in the above described manner.
The exemplary solvent that is suitable for making the dosage form composition comprises aqueous or organic solvent inert, used material in its not infringement system.Solvent extensively comprises: aqueous solvent, alcohol, ketone, ester, ether, aliphatic carbon hydrate, halogenated solvent, cycloaliphatic, aromatic series, heterocyclic solvents and composition thereof.Typical solvent comprises, acetone, DAA, methanol, ethanol, isopropyl alcohol, butanols, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl iso-butyl ketone (MIBK), methyl propyl ketone, normal hexane, normal heptane, ethylene glycol monomethyl ether, the glycol monomethyl ethylhexoate, dichloromethane, dichloroethanes, dichloropropane, the carbon tetrachloride nitroethane, the nitropropane sym-tetrachloroethane, ether, isopropyl ether, cyclohexane extraction, cyclooctane, benzene, toluene, Petroleum, 1, the 4-dioxane, oxolane, diethylene glycol dimethyl ether, water, contain inorganic salt, as sodium chloride, the aqueous solvent of calcium chloride etc., and composition thereof, as acetone and water, acetone and methanol, acetone and ethanol, dichloromethane and methanol, with dichloroethanes and methanol.
An important consideration in the present invention practice is the physical state of the opioid that will send by dosage form.In some instantiation, opioid becomes pasty state or is in a liquid state.In this case, solid dosage forms is not suitable for practice of the present invention.Use should be replaced and the pasty state of delivered substance or the dosage form that is in a liquid state can be used for.
The invention provides the liquid preparation of material, itself and oral osmotic device use together.The oral osmotic device of delivering liquid preparation and to use its method be existing known, the United States Patent (USP) 6419952,6174547,6551613,5324280,4111201 that has as following Alza Corp. and 6174547 description and claimed.Utilize oral osmotic device can in International Application No. WO 98/06380, WO98/23263 and WO99/62496, find with the method for the release rate delivering therapeutic agents of rising.
Be used for exemplary liquid-carrier of the present invention and comprise lipophilic solvent (as oil and fat), surfactant and hydrophilic solvent.As, exemplary lipophilic solvent includes but not limited to Capmul PG-8, CaprolMPGO, Capryol 90, Plurol Oleique CC 497, Capmul MCM, Labrafac PG, N-decanol, Caprol 10G10O, oleic acid, vitamin E, Maisine 35-1, Gelucire 33/01, and Gelucire 44/14, lauryl alcohol, Captex 355EP, Captex500, Capylic/Caplic triglyceride, Peceol, CaprolET, Labrafil M2125CS, Labrafac CC, Labrafil M 1944 CS, Captex 8277, Myvacet 9-45, isopropyl Nyristate, Caprol PGE 860, olive oil, Plurol Oleique, Oleum Arachidis hypogaeae semen, Captex 300Low C6, and capric acid.
As, exemplary surfactant comprises but is not limited to vitamin E TPGS, Cremophor (EL, EL-P and RH40 level), Labrasol, tween (20,60,80 grades), Pluronic (L-31, L-35, L-42, L-64 and L-121 level), Acconon S-35, Solutol HS-15 and Span (20 and 80 grades).As, exemplary hydrophilic solvent includes but not limited to isosorbide, dimethyl ether, Polyethylene Glycol (300,400,600,3000,4000,6000 and 8000 grades of PEG) and propylene glycol (PG).
Those of skill in the art can understand, can use any preparation that contains the opioid agent that enough is dissolved in the liquid-carrier among the present invention, are used for to patient's administration and are used in permeable mass.In exemplary instantiation of the present invention, liquid-carrier is PG, Solutol, Cremophor EL or its combination.
Also can comprise as extra excipient, as antioxidant, penetration enhancers etc. according to liquid preparation of the present invention.Antioxidant is used for slowing down or effectively stops the speed of the material autoxidation that any capsule exists.Representational antioxidant comprises: ascorbic acid; Alpha tocopherol; Ascorbyl palmitate; Ascorbate; Erythorbate; Butylated hydroxyanisole; Butylated hydroxytoluene; Nordihydroguiaretic acid; The ester of Bulbus Allii acid, it contains at least 3 carbon atoms, contains to be selected from following member: propyl gallic acid ester, octyl group epicatechol gallate, decyl epicatechol gallate, decyl gallic acid; 6-ethyoxyl-2,2,4-trimethyl-1,2-dihydro-guinoline; N-acetyl-2,6-two-tert-butyl-para-aminophenol; Butyl tyrosine; 3-tertiary butyl-4-hydroxy methoxybenzene; 2-tertiary butyl-4-hydroxy methoxybenzene; 4-chloro-2, the 6-DI-tert-butylphenol compounds; 2, the 6-di-t-butyl is right-methoxyphenol; 2,6-di-t-butyl p-Cresol; Poly-antioxidant; The physiologically acceptable salt of trihydroxy Ding Nei-phenyl ketone of ascorbic acid, arabo-ascorbic acid and ascorbic acid ethyl ester; Calcium ascorbate; Sodium ascorbate; Sodium sulfite; Or the like.As, the amount that is used for antioxidant of the present invention be the chamber have composition total weight about 0.001% to 25%.Antioxidant is known in prior art U.S. Patent No. 2707154,3573936,3637772,4038434,4186465 and 4559237, and every piece of document is all included this paper reference in full in.
Liquid preparation of the present invention comprises penetration enhancers, and medicine is absorbed in applied environment easily.Can open the what is called " closely node " in the gastrointestinal tract or revise the effect of cell component as, this reinforcing agent, as the p-glycoprotein etc.Suitable reinforcing agent comprises the alkali metal salt of following acid: salicylic acid, and as sodium salicylate, sad or capric acid, as sodium caprylate or Capric acid sodium salt, etc.Reinforcing agent comprises as bile salts, as sodium deoxycholate.Various p-glycoprotein regulators have description in U.S. Patent No. 5112817 and 5643909.Various other absorb the enhancing chemical compound and material has description in U.S. Patent No. 5824638.Reinforcing agent can mix use separately or with other reinforcing agents.
In some instantiation, material of the present invention comes administration with self-emulsifiable preparation.Other liquid-carriers of picture, surfactant is used to prevent cohesion, reduces the surface tension between composition, the free-flow of enhancing ingredients, and the reduction composition is trapped in the probability in the dosage form.Emulsion of the present invention comprises can carry out emulsive surfactant.Except surfactant listed above, exemplary surfactant also comprises: the Oleum Ricini of polyization that contains 9 to 15 moles oxirane, the sorbitan monopalmitate of polyization that contains 20 moles oxirane, list and tristearate, the sorbitan monostearate of polyization that contains 4 moles oxirane, the sorbitan trioleate of polyization that contains 20 moles oxirane, poly(ethylene oxide) Laurel ether, the stearic acid of polyization that contains 40 to 50 moles oxirane, contain 2 moles oxirane polyization stearyl alcohol and contain the poly(ethylene oxide) carburetion alcohol of 2 moles of ethylene oxide.Surfactant can derive from Atlas Chemical Industries.
Medicine emulsification preparation of the present invention can comprise oil and non-ionic surface active agent at first.The oil phase of Emulsion comprises any pharmaceutically acceptable oil, and it does not mix with water.Oil can be edible liquid, as the nonpolar ester of unsaturated fatty acid, and the derivant of these esters, or the mixture of these esters.Oil can be plant, mineral, animal or from the oil of ocean.Except surfactant listed above, non-toxic oil also can comprise: Oleum Arachidis hypogaeae semen, Oleum Gossypii semen; Oleum sesami, Semen Maydis oil, almond oil; mineral oil, Oleum Ricini, Oleum Cocois; Petiolus Trachycarpi oil; cupu oil, safflower, the glycerol list of 16 to 18 carbon and the mixture of diester; unsaturated fatty acid; fractionated triglyceride in the Oleum Cocois, fractionated triglyceride liquid from the fatty acid of 10 to 15 carbon atoms of short chain, acetylizad monoglyceride; acetylizad diglyceride; acetylizad triglyceride, olein (being also referred to as triglyceride), palmitin (being also referred to as tripalmitin); tristerin (being also referred to as glyceryl tristearate); lauric acid hexyl ester, oleic acid oleic alcohol ester, the ethoxyquin glycerol of the glycolysis of natural oil; the branching fatty acid that has the oxirane of 13 molecules, and decyl oleate.The oil in the emulsification preparation or the concentration of oily derivant are extremely about 40wt% of about 1wt%, and the wt% of all the components in the emulsification preparation equals 100wt%.Oil is disclosed in the Pharmaceutical Sciences of the Remington of Mark Publishing Co. publication, 17 editions, pp.403-405 (1985), Van Nostrand Reinhold Co, the Encyclopedia of Chemistry of the Van Nostrand Reinhold that publishes, 4 editions, pp.644-645 (1984), and in the U.S. Patent No. 4259323.
According to treatment situation and required administration cycle, as per 12 hours, per 24 hours etc., the amount of including the opioid in the dosage form of the present invention in was generally about 10% to about 90% of composition weight.According to the dosage of the opioid of required administration, but one or more dosage forms of administration.
Osmotic dosage form of the present invention have two kinds multi-form, soft capsule form (as shown in Figure 3) and form of hard gelatin capsules (as shown in Figure 4).Used preferred its final form of soft capsule of the present invention comprises a lamellar body.A slice body capsule is sealed to, and the pharmaceutical preparation of this paper is wrapped in the capsule.Capsule can be made by several different methods, comprises plate method, rotary die method, reciprocal mould method and continuation method.The example of plate method is as follows.Dull and stereotyped process is to use a mold.The warming thin slice for preparing capsular thin layer formation material is placed on the lower mould, and preparation waters thereon.Second thin slice that thin layer forms material is placed on the preparation under the top layer mould.Under the condition that heats or do not heat, mould places under the pressure and exerts pressure, and forms the unit capsule.Wash capsule with solvent, outside capsule, remove unnecessary preparation, air dried capsule is made capsule with semi-transparent wall.The rotary die process makes it to draw between a pair of rotary die and injection wedge with the thin film of two successive capsule thin layers formation materials.In dual operation simultaneously, capsule is filled and sealed into to this method.In the method.The capsule thin layer forms the thin film of material on guide roller, descends between injection wedge and rotary die then.
Gravity flows in the forward configuration pump encapsulated preparation.Pump is measured preparation by the injection wedge and is entered in the thin layer between rotary die.The wedge bottom comprises little opening, arranges along the mould bag of rotary die.Preparation to pumping is exerted pressure, and makes thin slice enter the mould bag, and at this moment that the chances are is semi-enclosed for capsule, and wherein capsule is filled simultaneously, is shaped, is sealed and downcuts from the thin slice that thin layer forms material.By on rotary die, pressing and, coming seal capsule thus by adding the thin slice that thermal wedge limit thin layer forms material with machinery.After the preparation, the capsule of filling preparation is dry in forced air, forms semi permeable thin film with regard to capsuleization.
Back and forth the mould method is made capsule by two thin film that form the capsule layer material between a cover vertical mold.Mould is closed, opens and is closed as successive vertical flat board along thin film formation capsule by rows.Fill this capsule and when this capsule moves past mould with preparation of the present invention, to their seal, molding, and downcut from mobile thin film, become the capsule that is full of preparation.Semi-transparent capsule shape straticulation is coated with thereon to produce capsule.This continuous process is a kind of manufacturing system, and it also can use rotary die, and except liquid is bundled into capsule, also has extra feature, and promptly this process can continue to inject the active agent of powdered in soft capsule.The capsule that continuous process is filled with is bundled into capsule with semi-transparent poly material, produces capsule.The process of producing soft capsule has description in U.S. Patent No. 4627850 and U.S. Patent No. 6419952.
But dosage form of the present invention also can be prepared by injection molding technology by injection moulding composition.But being provided for injection moulding goes into the injection moulding composition of semipermeable membrane and comprises that thermoplastic polymer or said composition contain the mixture of thermoplastic polymer and optional injection moulding component.The thermoplastic polymer who is used for this purpose contains the polymer with low softening point, as is lower than 200 degrees centigrade, preferably in 40 degrees centigrade to 180 degrees centigrade scope.Polymer is synthetic resin preferably, the resin of addition multimerization, as polyamide, derive from the resin of diepoxide and elementary chain alkanolamide, the resin of glycerol and phthalic anhydride, poly-methane, polyvinyl resin, end has free or the carboxyl of esterification or the fluoropolymer resin of Carboxylamide group, as have acrylic acid, acrylamide, acrylate, polycaprolactone and and dilactide, diglycolide, the copolymer of valerolactone and decalactone, resin combination, it contains polycaprolactone and polyepoxide, and resin combination, it contains polycaprolactone, polyalkoxide, as poly(ethylene oxide), poly-(cellulose) is as poly-(HYDROXY PROPYL METHYLCELLULOSE), poly-(hydroxy ethylmethylcellulose) and poly-(hydroxy propyl cellulose).Film forms compositions and comprises that optional film forms composition, as Polyethylene Glycol, Pulvis Talci, polyvinyl alcohol, lactose or polypropylene ketopyrrolidine.The compositions that is used to form the injection moldable polymers compositions can contain 100% thermoplastic polymer.In another embodiment, compositions contains 10% to 99% thermoplastic polymer and 1% to 90% different polymer, and summation equals 100%.The present invention also provides thermoplastic polymer's compositions, and it contains 1% to 98% the first thermoplastic polymer, 1% to 90% different second polymer and 1% to 90% different terpolymer, and summation equals 100%.
Representational compositions contains 20% to 90% thermoplastic polycaprolactone and 10% to 80% poly-(epoxide); Compositions contains 20% to 90% polycaprolactone and 10% to 60% poly-(oxirane), and the composition sum equals 100%; Compositions contains 10% to 97% polycaprolactone, 10% to 97% poly-(epoxide) and 1% to 97% poly-(oxirane), and all the components sum equals 100%; Compositions contains 20% to 90% polycaprolactone and 10% to 80% poly-(hydroxy propyl cellulose), and all the components sum equals 100%; And compositions contains 1% to 90% polycaprolactone, 1% to 90% poly-(oxirane), 1% to 90% gathers (hydroxy propyl cellulose) and 1% to 90% poly-(oxirane), and all the components sum equals 100%.Described percent is percetage by weight wt%.
In another embodiment of the invention, by in the blender of routine, as Moriyama
TMBlender, at 65 degrees centigrade to 95 degrees centigrade following blend compositions, it contains 63wt% polycaprolactone, 27wt% poly(ethylene oxide) and 10wt% Polyethylene Glycol, can prepare injection moulding thus so that the compositions of film to be provided, wherein each composition adds blender in proper order with following interpolation, polycaprolactone, poly(ethylene oxide) and Polyethylene Glycol.In one embodiment, the speed with 10 to 20rpm was mixed all the components 135 minutes in rotator.Then, under 80 degrees centigrade to 90 degrees centigrade, mixture added Baker Perkins Kneader
TMIn the extruder, pump speed 10rpm and velocity of rotation 22rpm is cooled to 10 degrees centigrade to 12 degrees centigrade then reaches consistent temperature.Then, the compositions that cooling was pushed adds in the Albe granulator, makes the ball that length is 5mm at 250 degrees centigrade.Injection machine Arburg Allrounder then packs ball under 200 degrees Fahrenheits to 350 degree centigrade (93 degrees centigrade to 177 degrees centigrade)
TMIn, be heated to the melt polymerization compositions, with high pressure with at a high speed with in the liquid polymeric compositions adding mold cavity, up to filling with mould, the compositions that contains polymer is solidified with the shape of preliminary election.Injection parameters comprises that the band temperature in 1 district to 5 district of tube is that 195 degrees Fahrenheits (91 degrees centigrade) to 375 degrees Fahrenheits (191 degrees centigrade), injection moulding pressure is that 55cm3/s and molding temperature are 75 degrees centigrade for 1818bar, speed.Injection moulding composition and injection moulding process have description in U.S. Patent No. 5614578.
Perhaps capsule can be made two parts easily, wherein a part (" lid ") slips over and covers on another part (" main body "), as long as but capsule is subjected to the power deformable of extension layer, and sealing is leaked between main body and lid compression section to prevent liquid, active agent.Two parts contain the inner chamber of liquid, active ingredient fully around coating, it can contain useful additive.Inject the preparation of preliminary election in main body after, two parts can lump together.By slide or with lamination on body layer, seal cover and main body are assembled thus, thus fully around and the coating active agent.
The wall thickness of soft capsule is usually greater than the wall thickness of hard capsule.As, the thickness of soft capsule on the order of magnitude of 10-40 mil, normally about 20 mils, and the thickness of hard capsule is on the order of magnitude of 2-6 mil, normally about 4 mils.
In an embodiment of sosimetric system, but soft capsule can be single unit configuration and can center on the asymmetric water active layer that has as extension layer.But extension layer generally is that asymmetrical, thicker part is away from outlet.The water active layer is drawn and/or when absorbing external fluid, and its expansion also applies propelling pressure and extrudes active ingredient from outlet to capsule wall and optional barrier layer.The existence of asymmetric layer can guarantee to send the reagent of maximal dose from dosage form, move away from the thicker layer segment expansion of gateway and to outlet.
In another configuration, but form that can discontinuous part forms extension layer, makes it not exclusively to surround the capsule of optional barrier layer coating.But extension layer can be a discrete component, and it forms to be fit to the shape of capsule when the contact surface.To form recessed surface, it is complementary to the capsular outer surface of barrier layer coating, but can make extension layer easily thus by in flakes.
Proper tools, as produce the conventional protruding stamping machine of pressure in flakes, provide necessary complementary shape but can be extension layer.In this case, but extension layer granulation and compression, rather than form coating.But extension layer is known by the method for shaping in blocks, as in U.S. Patent No. 4915949,5126142,5660861,5633011,5190765,5252338,5620705,4931285,5006346,5024842 and 5160743 description being arranged.
In some embodiments, can at first barrier layer be coated on the capsule, in blocks then, but extension layer is connected on the capsule that scribbles obstacle by biocompatible binding agent.Suitable bonding comprise as, gelatinized corn starch, aqueous gelatin solution, aqueous gelatin/glycerite, based on the binding agent of acrylic acid-ethylene acetic acid, as the aqueous solution of Duro-Tak binding agent (National Starch and Chemical Company), water solublity hydrophilic polymer, as HYDROXY PROPYL METHYLCELLULOSE, hydroxy-methyl cellulose, hydroxy ethyl cellulose etc.Use semi-permeable layer coating intermediate dosage form then.Opening is opened on capsular limit or end, but facing to the extension layer part.But when extension layer was inhaled fluid, it can expand.Because the semi-permeable layer constraint is arranged, and it can compress the capsule that is surrounded by obstacle and extrude liquid, active ingredient to applied environment in capsule during expansion.
Hard capsule is made up of two parts usually, lid and main body, and after the appropriate formulation of bigger main body injection preliminary election, it can lump together.Can on body layer, realize by slip or with lamination, thereby fully around coating useful reagent preparation.As, in the bath that the rustless steel pressing mold is immersed in the solution that contains capsule thin slice formation material,, prepare hard capsule thus with this material coating mould.In air-flow, reclaim then, cool off and drying die.Peel capsule and cut out the thin sheet element that has inner chamber with generation from mould.Seal cover is made in a similar manner at the joint lid that has on the main body of preparation.The capsule that will seal and fill with semi-transparent thin slice is made capsule then.Semi-transparent thin slice can be applicable to the capsule halves before or after the part, and is integrated into final capsule.In another embodiment, hard capsule can be fabricated to each part and has the lock ring of coupling, the main body after it can combine and pin eclipsed lid and inject preparation at its open end.In this embodiment, the lock ring of a pair of coupling forms cover and main part, and these rings provide capsule safety is contained in together locking mode.Capsule can inject preparation by hand, or their available machines used are injected preparation.In final production, use semi-transparent thin slice, but its permeate fluid and substantially see through useful reagent is made capsule with hard capsule.The method that forms the hardcoat dosage form has description in U.S. Patent No. 6174547, U.S. Patent No. 6596314,6419952 and 6174547.
Hard and soft capsule can contain just like, gelatin; Have the viscosity of 15 to 30 millipoises and the gelatin of blank intensity of 150 grams at the most; Gelatin with 160 to 250 blank values; The compositions that contains gelatin, glycerol, water and titanium dioxide; The compositions that contains gelatin, Erythrosin, ferrum oxide and titanium dioxide; The compositions that contains gelatin, glycerol, sorbitol, potassium sorbate and titanium dioxide; The compositions that contains gelatin, Radix Acaciae senegalis G ﹠ W; Or the like.The material that is used to form the capsule film is disclosed in U.S. Patent No. 4627850 and 4663148.Perhaps, capsule can be made (as the product of making referring to, BioProges plc) by the material except gelatin.
For example, capsular size is generally about 3 to about 22 minims (1 minim equals 0.0616ml), and it is shaped as ellipse, rectangle or other.They can be the shape of standard and the size of various standards, usually called after (000), (00), (0), (1), (2), (3), (4) and (5).Maximum numerical value is corresponding to the size of minimum.Also available off-gauge shape.For soft capsule or hard capsule, specific if desired application can be used unconventional shape.
Permeable mass of the present invention can comprise semipermeable membrane, and it can see through outside biofluid and not see through the opioid preparation substantially.Being used for film forming selectively penetrating compositions is not corrodible basically, and is insoluble to biofluid in the osmosis system duration.Semipermeable membrane comprises the compositions that does not injure host, opioid preparation, osmopolymer, penetrating agent etc.In this paper other parts disclosure is arranged as the material that forms semipermeable membrane.
Semipermeable membrane also can comprise flux-regulating agent.The material that is used for flux-regulating agent has disclosure in this paper other parts.Thereby can be used for forming semipermeable membrane material flexible for semipermeable membrane brings and extensible character and also disclosure is arranged in this paper other parts.
Semipermeable membrane centers on and has formed a cell, contain one layer or more, but one of them is an extension layer, and in some embodiments, it can contain osmotic agent.But the compositions of being somebody's turn to do extension layer has disclosure in this paper other parts.
In the embodiment of some solid and liquid, dosage form can further comprise barrier layer.In some embodiments, and during the delivery of active preparation, but barrier layer can be subjected to the extension layer application of force and be out of shape, and will not see through (or few seeing through) but be present in fluid and material in extension layer, liquid active ingredient and the applied environment.If do not damage the delivery rate of active ingredient, then can allow barrier layer permeability to a certain degree.But preferably during the delivery of active preparation, barrier layer fully can not be by fluid and the material in its transmission dosage form and the applied environment.But barrier layer is subjected to the extension layer application of force and is out of shape, thereby the compression capsule is extruded liquid, active ingredient from outlet.In some embodiments, barrier layer is deformed to a kind of degree, but makes it and will form the regional seal of outlet between extension layer and semi-permeable layer.In this mode, but barrier layer distortion or rheology extension layer and semi-permeable layer area exposed when limited degree seals initial formation opening, as by brill etc., or in the initial manipulation stage.During sealing, be to pass semi-permeable layer but liquid infiltration enters unique path of extension layer, but and do not have withdrawing fluid to enter extension layer by opening.
The suitable material that forms barrier layer comprise as, polyethylene, polystyrene, ethylene-vinyl acetate copolymer, polycaprolactone and Hytrel
TMPolyester synthetic rubber (Du Pont), cellulose acetate, the imitative rubber (as described in U.S. Patent No. 5024842) of cellulose acetate, cellulose acetate propyl ester, cellulose acetate butyl ester, ethyl cellulose, the imitative rubber of ethyl cellulose are (as 10Colorcon, West Point, the Surelease that Pa supplied
TMOr FMC Corp., Philadelphia, the Aquacoat that Pa. supplied
TM), the copolymer of copolymer, methyl methacrylate and the ethyl propylene acid esters of NC Nitroncellulose, polylactic acid, poly--glycolic, poly (lactic acid-glycolic acid) copolymer, collagen, polyvinyl alcohol, polyvinyl acetate, polyethylene vinyl acetic acid esters, polyethylene p-phthalic acid, polybutadiene styrene, polyisobutylene, the different propylene copolymer of polyisobutylene, polyethylene chlorine, polyvinylene chloro-ethylene chloromethylated copolymer, acrylic acid and methacrylic acid esters, acrylate rubber be (as RohmPharma, Darmstaat, the Eudragit that Germany is supplied
TM), acrylic acid, silicone or the polyester of crosslinked acrylic acid, silicone or the polyester of copolymer, expoxy propane epoxyethane block copolymer, ethylene-vinyl alcohol copolymer, polysulfones, ethylene-vinyl alcohol copolymer, poly-inferior dimethylbenzene, polyalkoxysilane, polydimethylsiloxane, Polyethylene Glycol-silicone synthetic rubber, the electromagnetic radiation of polypropylene, expoxy propane and oxirane, heat cross-linking, butadiene styrene rubber, and above mixture.
Preferable material can comprise, the copolymer and the acrylate rubber of the copolymer of cellulose acetate, acrylic acid and methacrylate, methyl acrylate and ethyl propylene acid esters.Preferred copolymer comprises poly-(butyl methyl acrylate), (2-dimethyl aminoethyl) methacrylate, methyl methacrylate) 1: 2: 1,150000, it is sold with trade mark EUDRAGIT E; Poly-(ethyl acrylate, methyl methacrylate) 2: 1,800000, it is sold with trade mark EUDRAGIT NE 30D; Poly-(methacrylic acid, methyl methacrylate) 1: 1,135000, it is sold with trade mark EUDRAGIT L; Poly-(methacrylic acid, ethyl acrylate) 1: 1250000 sold with trade name EUDRAGITL; Poly-(methacrylic acid, methyl methacrylate) 1: 2135000 sold with trade name EUDRAGITS; Poly-(ethyl acrylate, methyl methacrylate, trimethyl amino-ethyl methacrylate chloride) 1: 2: 0.2,150,000, sell with trade name EUDRAGIT RL; Poly-(ethyl acrylate, methyl methacrylate, trimethyl amino-ethyl methacrylate chloride) 1: 2: 0.1,150000, it is sold with trade mark EUDRAGIT RS.Under each situation, ratio x: y: z represents the molar ratio of monomer unit, and last numeral is the mean molecule quantity numeral of polymer.The cellulose acetate of preferred especially plasticizer-containing is as acetyl tributyl citrate ester and ethylacrylic acid METH methacrylate copolymer, as EudragitNE.
Can be equipped with plasticizer as the previous materials of barrier layer, make the suitable distortion of barrier layer, thereby but the power that extension layer applies is come dispense liquid, active ingredient with the pressure formed cell of barrier layer that collapses.Typical plasticizer example is as follows: polyhydroxy-alcohol, glyceryl triacetate, Polyethylene Glycol, glycerol, propylene glycol, acetate, triacetin, triethyl citrate, acetyl triethyl citrate, glyceride, acetylizad monoglyceride, oil, mineral oil, Semen Ricini wet goods.According to the weight of material, plasticizer is sneaked in the material with the 10-50 percentage by weight.
Can pass through conventional coating method, described as U.S. Patent No. 5324280, but use the layer of various formation barrier layer extension layers and semi-permeable layer.Although but the barrier layer extension layer and the semi-permeable layer of example and description are suitable as monolayer, each of these layers can be made up of multilamellar.As for special application, wish with ground floor material coating capsule, thereby make the easier coating of the second layer with barrier layer penetration property.In this case, first and second layers contain barrier layer.But similar consideration can be applicable to semi-permeable layer and extension layer.
By power auger, laser bore, corrode corrodible element, extraction, dissolve, break or from the compositions wall flow pass, all can form outlet.As described in U.S. Patent No. 4200098, outlet can be the hole, and it waits and form by the sorbitol that pours off from film or layer, lactose.This patent disclosure the controlled hole of pore size, its by dissolving, extract or from wall, flow out material (as from cellulose acetate, flowing out sorbitol) and form.The preferred form that laser bores is an apply pulse laser, quickens to remove material from composition film, until desired depth, thereby forms outlet.
Fig. 5 A-5C shows the dosage form that another is exemplary, and it is existing known and in U.S. Patent No. 5534263,5667804 and 6020000 description is arranged.In brief, Fig. 5 A has shown the profile of the dosage form 80 before the digestion in gastrointestinal tract.Dosage form comprises the cylindric substrate 82 that contains material of the present invention.The end 84,86 of substrate 82 preferably the circle with protruding shape, guarantee easy digestion with this.Be with 88,90 and 92 around cylindric substrate, it is formed by the material in the water insoluble relatively environment.Suitable material has description in above-mentioned patent and other parts of this paper.
Shown in Fig. 5 B, after dosage form 80 digestion, begin corrosion with substrate 82 zones between 88,90,92.The corrosion of substrate is discharged in the gastrointestinal fluid environment material of the present invention.Shown in Fig. 5 C, when dosage form continued to pass through gastrointestinal tract, substrate continued corrosion.Here, corrosion substrate arrives to a certain degree, and dosage form is broken into 3 94,96,98.Corrosion lasts till every substrate part corrosion fully.From gastrointestinal tract, discharge afterwards and be with 94,96,98.
Other realizes that from peroral dosage form the lasting method that discharges medicine is existing known.For example, known have a disperse system, as accumulation body and matrix body, dissolution system is as capsule dissolves system (comprise as, " ball after a little while ") and stromatolysis system, dispersed/dissolved combined system and ion exchange resin system, it 1990 editions, has description at the PharmaceuticalSciences of Remington among the pp.1682-1685.The dosage form that makes according to these additive methods is included in the following extent and scope disclosed herein: this paper and the drug release characteristics that limits in the claims and/or plasma concentration feature are from literal or these dosage forms of having described of equal value.
In other instantiation of the inventive method, by using enteric coating, the sustained release forms of qualification can prevent alcoholic acid effect in the gastrointestinal tract.Alcohol, especially ethanol tend to be absorbed in upper gastrointestinal (especially stomach).Therefore, discharge in upper gastrointestinal at first by stoping medicine, the application of enteric coating can relax the influence of the alcohol of administering drug combinations to the sustained release forms of invention.
In preferred instantiation, enteric coating contains the intestinal polymer.Preferred intestinal polymer is not dissolved in ethanol rapidly, but can expand very slowly or dissolve.Other polymer or material can not weaken the performance of enteric coating in ethanol as long as add them with the intestinal polymer mixed.In some instantiation, selection can strengthen the performance of intestinal polymer in alcohol-water solution with the polymer or the material of intestinal polymer mixed.As, in instantiation, in alcohol-water solution, almost do not have or do not have swelling/deliquescent polymer or material and can mix well with the intestinal polymer.Need plasticizer,, prevent fragility as the PEG6000 of 1-20% level.Be suitable for intestinal polymer of the present invention and comprise cellulose acetate phthalate, make by Eastman Chemical as those.In some instantiation,,, or, can prepare the intestinal polymer by water dispersion as acetone or acetone mixture by solvent system.In some cases, utilize the compression compression molding techniques to prepare enteric coating.
In other instantiation of the present invention, non-intestinal polymer can be used for the coating sustained release forms, and thereby reduces the probability that alcohol-induced dose dumping discharges, the unexpected release of particularly alcohol induced dosage.In instantiation, available Eudragit RS 100 and Eudragit RL100.These polymer it is reported water insoluble, and slowly are dissolved in ethanol/water mixture.It is reported that they bring water permeability low and appropriateness respectively.In order to be used for continuous release tablet substrate, these can be water and in ethanol/water mixture the thin film of rational and effective limiting speed.This structure can discharge principle according to controlled dispersion and move.These thin film are usually by the water dispersion manufacturing and be furnished with plasticizer, as triethyl citrate and anti-binder, as Pulvis Talci.In another instantiation, the available cellulose acetate that contains the 24-28% acetyl group.This material it is reported water-soluble and is insoluble to ethanol/water mixture, thereby in dosage form and alcohol (especially ethanol) administering drug combinations, can reduce the probability that alcohol-induced dose dumping discharges.Non-intestinal polymer can be a solution, and it utilizes compression compression molding techniques coating or application.
In instantiation, the sustained release forms of the inventive method can be the substrate dosage form.The substrate dosage form comprises glue composition, control initial disruptive hydrophobic vehicle, medicine and diluent usually.Usually, according to the dosage form gross dry weight, the glue composition is that 20-60wt% and hydrophobic vehicle are 5-20wt%.These dosage forms can prepare by pelletize or combination drying and tablet forming.Perhaps, the preparation hot melt is pressed into the strip that can cut and injects capsule, produce dosage form of the present invention thus.
Suitable glue composition comprises:
1. HPMC (K4M, K100, mixture E5) of the different stage of molten and the viscosity of expanding for acquisition is ideal.HPMC is insoluble to ethanol, thereby can estimate in alcohol/water than discharging slowlyer in water.Can add HPC (from the Klucel of Hercules-Aqualon) and stop hydration rate.
2. the mixture of the poly(ethylene oxide) of different stage (can derive from the Polyox of Dow Chemical).Polyox is the swelling much less in alcohol/water than in water.The rank of suggestion is POLYOX WSR-205NF, WSR-1105 NF, WSR N-12K NF, WSR N-60K NF, WSR-301 NF, WSR-303 NF, WSR coagulating agent NF.These contain the preparation of 20-55% usually.
3.NaCMC (sodium carboxymethyl cellulose) is insoluble to ethanol, thereby may be not easy to take place in ethanol/water mixture dose dumping release.
4. alginic acid is insoluble to ethanol, swelling in water, thereby can estimate that swelling gets less in ethanol/water.
5. xanthan gum and guar gum substrate
6. polyvinyl alcohol it is reported water-solublely, but is insoluble to ethanol.
Because low dissolve with ethanol below is used for controlling disruptive hydrophobic vehicle in ethanol/water mixture equivalence or more effective;
(1.MC deriving from the methylcellulose of Dow Chemical, Methocel-A Premium )
Palmitostearate (Precirol ATO-5, Gattefosse)
Glyceryl Behenate (Compritol 888-ATO, Gattefosse)
4. calcium stearate
5. wax
6. plant and mineral oil
7. aliphatic alcohol
8. polycaprolactone
9.PLGA
10. Colophonium
In instantiation, hydrophobic vehicle comprises hydrophobic vehicle, and its fusing point is more than or equal to about 55 degrees centigrade.This hydrophobic vehicle includes but not limited to, paraffin wax white, stearyl alcohol, Cera Flava, Lubritab (vegetable oil), Colophonium, Brazil wax and castor oil hydrogenated.
Be used for the diluent of matrix formulations or inserts not appreciable impact release profiles usually., careful these excipient of selection under the situation that has alcohol, but the initial sum release profiles in the diluent appreciable impact controlled release substrate.In instantiation, select useful diluent, it has lower dissolubility in alcohol-water solution than in water, thereby makes nuclear core aquation, therefore limit drug dissolving in the alcohol-water solution environment.In preferred instantiation, useful diluent comprises mannitol.
More not preferred following hydrophobic vehicle is used for the present invention:
1.EC (from the ethyl cellulose of Dow Chemical) is used usually, but it is dissolved in ethanol.
2. hydrogenation polyoxy 60 Oleum Ricini.
U.S. Patent No. 5871778 and 5656299 discloses and continues microball preparation has the zero level of being almost to patient's administration time the active component release rate.U.S. Patent No. 5654008,5650173,5770231,6077843,6368632 and 5965168 discloses the controllable delivery that continues the release microparticles compositions and be used for active agent.
In another instantiation, the infiltration granule can be used in the practice of the present invention.With opioid Wurster-coating on the seed that enough osmotically actives are arranged or other materials of superfine quality.Then, by another Wurster-coating process semipermeable membrane is wrapped.For the latter, remove product in the different time or the stage of coating, thereby obtain a series of coating thicknesses.During aquation, system is put into water, owing to the osmotic pressure effect is broken and discharged medicine.Rupture time and film thickness on each granule are proportional.These granules can be chosen wantonly and comprise some and without any can be as the semi-transparent coating of instantaneous relase composition, these granules can incapsulate to form the instantiation of sustained release forms of the present invention.
If the medicine that utilizes the infiltration granule to load is too limited, then available then extruding-spheronizing technology produces granule.The advantage of this method is that more the multiple medicines thing can be integrated into granule, and a less coating process is arranged.Preferably be used to push-carrier of spheronizing technology can include but not limited to PLGA R208, Colophonium and other high molecular weight materials.Also available other are produced granule technology, do not contain the nuclear core of medicine as coating.Contain that the granule of medicine is available alternatively not to present semipermeable film coating to water, and disperse and infiltration comes sustained release by uniting.In instantiation, sclerosing agent and/or hydrophobic material can be integrated into and continue in the releasing agent structure, prevent that alcohol-induced dose dumping from discharging.Preferred setting agent and/or hydrophobic material include but not limited to, aliphatic alcohol, wax, oil and Biodegradable material; More preferably this material includes but not limited to, hard ester alcohol, Brazil wax, castor wax and Colophonium.
In instantiation, also can use the gastric retention system.Routine gastric retention system realizes gastric retention according to its size (promptly greater than pyloric ostium) and density (being lighter than the GI content makes it to float).The available polymer of system includes but not limited to, poly(ethylene oxide) (Polyox), HPC, HPMC, polyvidone, CMC sodium, ethyl cellulose etc.The adding of hydrophobic material or wax can be promoted the performance of these materials (it tends to form more weak glue in alcohol-water solution, thereby can cause not satisfied performance)., hydrophobic material can significantly increase this gastric retention system further enters the downstream from stomach risk.
The gastric retention system of other types comprises the release portion of adherent sturdy frame and/or whole control.The release portion of these frameworks and/or whole control is preferably by forming the material of alcohol-water solution relative insensitivity, thus the character of maintenance gastric retention and sustained release.
It should be understood that described dosage form and preparation strategy only enumerated the dosage form that will realize material administration of the present invention in a large number herein.The pharmaceutical field technical staff can identify other appropriate formulation strategies, especially because be not that all preparation strategies can both be used for all opioids.Also can in the technical scope of those of ordinary skill, be optimized in the practice of the present invention.
IV. embodiment
Embodiment 1: hydromorphone tablet, double-deck 16mg system
The hydromorphone sustained release forms of invention is conditioned, designs and is shaped to be become osmotic drug and sends body, and it is prepared as follows: at first, and pharmaceutical compositions.8.98kg dihydromorphinone hydrochloride, 2.2kg are called as the polyvidone (polyvinylpyrrolidone) of K29-32 and the poly(ethylene oxide) of 67.06kg mean molecule quantity 200000 joins in the basin of liquid bed nodulizer.Then, 6.0kg is called as K29-32's and polyvidone (polyvinylpyrrolidone) with 40000 mean molecule quantities is dissolved in the 54.0kg water with the preparation binder solution.By spraying 18.0kg binder solution dried feed is carried out fluidized bed prilling.Then, dry wet particle is up to acceptable water content, and with the mill sizing that is fit to 7-mesh sieve in comminutor.Then granule is passed in the blender, mix as the butylated hydroxy-methylbenzene of antioxidant with 16g, and lubricated with the 0.20kg magnesium stearate.
Then, be prepared as follows the propelling compositions: 24.0kg sodium chloride and the utilization of 0.32kg Black Rouge have the Quadro Comil sizing of 21-mesh sieve.The material that sifts out, 1.6kg are called as 2910 HYDROXY PROPYL METHYLCELLULOSE and the poly(ethylene oxide) of 51.44kg mean molecule quantity about 7000000 joins in the basin of liquid bed nodulizer.Then, preparation binder solution.Then, 6.0kg is called as HYDROXY PROPYL METHYLCELLULOSE 2910 and that have the 5cps average viscosity and is dissolved in the 54.0kg water with the preparation binder solution.By spraying 24.0kg binder solution exsiccant raw material is carried out fluidized bed prilling.Then, dry wet particle and comes sizing with the mill that is fit to 0.094 inch sieve up to acceptable water content in comminutor.Then granule is passed in the blender, mix with the butylated hydroxy-methylbenzene of 40g, and lubricated with the 0.20kg magnesium stearate.
Then, hydromorphone pharmaceutical composition and propelling compositions are compressed into two-layer nuclear core.At first, 150mg hydromorphone pharmaceutical composition is added in the mold cavity and carries out precompressed, adds 130mg then and advances compositions and this lamination is advanced diameter 11/32 ", standard concave, in the dual layer arrangement.
Dual layer arrangement is with semi-transparent wall coating.Wall forms material and contains 99% and be called as 398-10's and cellulose acetate and 1% with 39.8% average acetyl content is called as Polyethylene Glycol 3350 and that have 3350 mean molecule quantities.Wall forms compositions and is dissolved in the mixture of 96% acetone and 4% water, makes 6% solid solution.Wall being formed compositions in the pan coating machine is sprayed on the dual layer arrangement and, has used about 30mg film up to every on every side.
Pass semi-transparent wall and get out the exit passageway of a 0.64mm, make medicine layer and agent system external communications with laser.Under 45 ℃ and 45% relative humidity dry 72 hours to remove remaining solution.After the drying, dry tablet is 4 hours under 45 ℃ and suitable humidity.
Embodiment 2: release in vitro research-16mg hydromorphone
Carry out a series of solubility tests with the hydromorphone tablet of embodiment 1 and assess the influence of alcohol the release in vitro feature of the hydromorphone sustained release forms of the 16mg of containing hydromorphone of the present invention (for dihydromorphinone hydrochloride).In the aqueous solution that contains 0,4,20 and 40% volume ethanol, bathe the release of measuring dihydromorphinone hydrochloride in 24 hours with the dissolving of VII type.
The dihydromorphinone hydrochloride 16mg tablet of embodiment 1 is used for determining the release rate in 0%, 4%, 20% and 40% ethanol and accumulates release profiles.Point release rate result was used for 0% ethanol (water) condition since 0 month stabilization time.Other samples of utilization stable extension point since 0 month produce the release rate of 4%, 20% and 40% ethanol condition.The release rate condition is as follows: equipment: the USPVII type; Medium: the aqueous solution that contains 0%, 4%, 20% and 40% volume ethanol; Volume: 50mL; Temperature: 37 ± 0.5 degrees centigrade; Time point: 2,4,6,8,10,12,14,16,18 and 24 hours.
Attention: careful operation minimizes the evaporation of release rate medium.For preceding 6 intervals and last interval (2-12 hour and 24 hours), added the release rate medium in 30 minutes in each precontract at interval, and after finish at each interval, from release rate is bathed, take out the release rate test tube at once.For at interval 14,16 and 18, simultaneously with medium as in bathing, the release rate test tube was kept in bath about 6 and a half hours.
Medium is prepared as follows:
4% volume ethanol: join in the 3360mL water straight alcohol (Sigma-Aldrich, 200 checkings) of 140mL volume and mix homogeneously.
20% volume ethanol: join in the 2800mL water straight alcohol of 700mL volume and mix homogeneously.
40% volume ethanol: join in the 2100mL water straight alcohol of 1400mL volume and mix homogeneously.
Be prepared as follows sample: mix the sample solution in back injection 4% and 20% ethanol.Study fast to prove conclusively the accuracy of this method.Become two kinds of standard substance with the variable concentrations preparation in water with 40% ethanol dilution with 20%, and analyze by HPLC respectively, assessment % recovers and peak shape.Owing to observe the detached peaks of sample under the 40% alcoholic acid condition of existence, and do not observe in other sample solutions, the sample solution in 40% ethanol needs further to handle, and just so injection of the sample solution in 4% and 20% ethanol.
For avoiding detached peaks, be prepared as follows the sample solution in 40% ethanol: after being cooled to room temperature, the solution in the release rate test tube is recalled to 50ml and mix homogeneously with 40% ethanol water.Sample solution with the 2mL volume joins in the scintillation vial then.Evaporate sample solutions with vaporizer (SPD SpeedVac, SPD131DDA, RVT4104Refrigerated Vapor Trap, OFP-400, Thermo Sawant) 45 degrees centigrade of dryings.In the water add-back scintillation vial of 2mL volume and mix homogeneously.Then sample solution is expelled on the HPLC.
The HPLC condition
Post: Varian Inertsil Phenyl-3,5mm, 4.6 * 150mm
Mobile phase: 35% methanol, 65% buffer (0.1% sodium phosphate, 0.2% perfluoroetane sulfonic acid, sodium salt, pH=2.2)
Flow velocity: 1.5mL/ minute
Temperature: 45 degrees centigrade
Volume injected: 50mL
Wavelength: 280nm
Running time: 7 minutes
This test result as shown in Figure 6.For hydromorphone sustained release forms of the present invention, various ethanol waters do not cause dose dumping to discharge or uncontrollable release., observe, along with the increase of concentration of alcohol in the dissolve medium, release rate has the trend of increase.(6% label/hr), average release rate is maximum in 40% ethanol medium, and (about 10% label/hr) does not have influence (about 6% label/hr) in 4% ethanol medium with respect to 0% contrast.Correspondingly, as shown in Figure 1,, send the time (T90) of 90% medicine and in 4% medium, do not have influence, in 40% medium influence maximum with respect to contrast.Even for 40% ethanol condition, T90 is 12h.In addition, to 2 hours of tablet accumulation release time at interval (zero-time) have only minimum influence, reflecting does not have dose dumping to discharge concerning the concentration of alcohol of all assessments.
Table 1: hydromorphone 16mg tablet is summed up at the extracorporeal releasing characteristic of ethanol water
| Hydromorphone | Ethanol/water solution compositions (%v/v) | |||
| 0% (contrast) | 4％ | 20％ | 40％ | |
| T90(hr) | 18 | 18 | 15 | 12 |
| The accumulation % that located to discharge in 2 hours (% label) | ＜1 | ＜1 | ＜1 | 4 |
| | 6 | 6 | 7 | 10 |
| With respect to 0% alcoholic acid average release rate (%) | | 100 | 116 | 160 |
Embodiment 3: the release in vitro comparative study
As a comparison, utilize the dissolving of II type to bathe the dihydromorphinone hydrochloride that assessment discharges in Little water. (Vodka) (27%v/v ethanol) and water from Palladone XL 32mg capsule, come the hydromorphone tablet of comparing embodiment 1.
Solubility parameter is as follows: dissolution equipment: Varian VK7010 dissolving unit and VK8000 Autosampler; Medium: be respectively water and Little water. (Pavlova, 40% volume ethanol); Volume: 900mL; Mixing speed: 50rpm; Volume aspirated: 5mL; Temperature: 37 ± 0.5 degrees centigrade; Time point: T=1,2,4,6,10,14,18 and 24 hours.Attention: test result shows that the determining alcohol of Pavlova only is 27%.
Because the color of Little water. is disturbed, analyze the sample solution in the front evaporator Little water., detailed process is as follows: with Autosampler with the 5mL volume sample solution test tube of packing into.After being cooled to room temperature, the sample solution of 2mL volume is joined in the scintillation vial.Evaporate sample solutions with vaporizer (SPD SpeedVac, SPD131DDA, the cold Refrigerated Vapor of RVT4104 Trap, OFP-400, Thermo Savant) 45 degrees centigrade of dryings.In the water add-back scintillation vial of 2mL volume and mix homogeneously.Then sample solution is expelled on the HPLC.Sample solution in the water is cooled to room temperature and is expelled on the HPLC.
Sample solution in the water is so injection just, and the sample solution in the Little water. evaporates and water refills, and prepares sample thus.Carry out simple study on accuracy, show that two kinds of sample products do not have difference.For the sample solution in the water, the evaporation drying standard substance reach 100.04 and 180.07mg/mL, mend 2mL water respectively, carry out HPLC behind the mixing and analyze.For the sample solution in the Little water., the standard substance of 250.13mg/mL are diluted to 50.03mg/mL with Little water., triplicate, and evaporation drying is mended 2mL water, carries out HPLC behind the mixing and analyzes.The assessment equivalence is restorative between two sample goods.
Measure the sample solution volume of water and Little water. after 24 hours, calculate evaporation rate by following formula: draw evaporation rate=(900-final volume-8 * 5)/24 hours 8 * 5=5mL for 8 time points at every turn based on linear evaporation.Evaporate with the solubility curve calculation correction.The experiment of water and Little water. is measured for three times respectively and is determined the sample volume aspirated.
The HPLC condition is as follows:
Post: but Varian Znersil Phenyl-3,5mm, 4.6 * 150mm
Mobile phase: 35% methanol, 65% buffer (0.1% sodium phosphate, 0.2% perfluoroetane sulfonic acid, sodium salt, pH=2.2)
Flow velocity: 1.5mL/ minute
Temperature: 45 degrees centigrade
Volume injected: 100mL
Wavelength: 280nm
Running time: 6.5 minutes
Because low in time point sample solution concentration early, volume injected has been increased to 100mL.When being exposed to 27% ethanol, listed and shown in Figure 7 as table 2, with respect to 21% label in the water, Palladone XL has sent 100% label in two hours.
Table 2:Palladone XL 32mg capsule is summed up at the extracorporeal releasing characteristic based on alcoholic acid solution
| Palladone XL | Ethanol/water solution compositions (%v/v) | |
| 0% (contrast) | 27％ | |
| T90(hr) | ＞24 | 1 |
| The accumulation % that located to discharge in 2 hours (% label) | 21 | 100 |
Embodiment 4: hydromorphone tablet, double-deck 16mg system
The hydromorphone sustained release forms of invention is conditioned, designs and is shaped to be become osmotic drug and sends body, and it is prepared as follows: at first, and pharmaceutical compositions.8.98kg dihydromorphinone hydrochloride, 2.2kg are called as the polyvidone (polyvinylpyrrolidone) of K29-32 and the poly(ethylene oxide) of 67.06kg mean molecule quantity 200000 joins in the basin of liquid bed nodulizer.Then, 6.0kg is called as K29-32's and polyvidone (polyvinylpyrrolidone) with 40000 mean molecule quantities is dissolved in the 54.0kg water with the preparation binder solution.By spraying 18.0kg binder solution to dried feed pelletize in fluid bed.Then, dry wet particle is up to acceptable water content, and with the mill sizing that 7-mesh sieve is housed in comminutor.Then granule is passed in the blender, mix as the butylated hydroxy-methylbenzene of antioxidant with 16g, and lubricated with the 0.20kg magnesium stearate.
Then, be prepared as follows the propelling compositions: 24.0kg sodium chloride and the utilization of 0.32kg Black Rouge have the Quadro Comil sizing of 21-mesh sieve.The material that sifts out, 1.6kg are called as 2910 HYDROXY PROPYL METHYLCELLULOSE and the poly(ethylene oxide) of 51.44kg mean molecule quantity about 7000000 joins in the basin of liquid bed nodulizer.Then, preparation binder solution.Then, 6.0kg is called as HYDROXY PROPYL METHYLCELLULOSE 2910 and that have the 5cps average viscosity and is dissolved in the 54.0kg water with the preparation binder solution.By spraying 24.0kg binder solution in fluid bed to the dried feed pelletize.Then, dry wet particle and comes sizing with the mill that 0.094 inch sieve is housed up to acceptable water content in comminutor.Then granule is passed in the blender, mix with the butylated hydroxy-methylbenzene of 40g, and lubricated with the 0.20kg magnesium stearate.Then, hydromorphone pharmaceutical composition and propelling compositions are compressed into two-layer nuclear core.At first, 150mg hydromorphone pharmaceutical composition is added in the mold cavity and carries out precompressed, adds 130mg then and advances compositions and this lamination is advanced diameter 11/32 ", standard concave, in the dual layer arrangement.
Dual layer arrangement is with semi-transparent wall coating.Wall forms material and contains 99% and be called as 398-10's and cellulose acetate and 1% with 39.8% average acetyl content is called as Polyethylene Glycol 3350 and that have 3350 mean molecule quantities.Wall forms material and is dissolved in the mixture of 96% acetone and 4% water, makes 6% solid solution.Wall being formed material in the pan coating machine is sprayed on the dual layer arrangement and, has used about 33mg film up to every on every side.Pass semi-transparent wall and get out the exit passageway of a 0.64mm, make medicine layer and agent system external communications with laser.Under 45 ℃ and 45% relative humidity dry 72 hours to remove remaining solution.After the drying, dry tablet is 4 hours under 45 ℃ and suitable humidity.
Then with the exsiccant tablet of normal complexion clarification coating coating is arranged.Yellow Opadry II colored coating is called as Y-30-12863-A.14.4kg yellow Opadry II color contamination is gone in the 105.6kg water, forms painted suspension.In the pan coating machine, be sprayed onto painted suspension on the dry tablet agent and, used about 18mg on every side up to every.Then, sneak in the 45.6kg water, prepare the clarification coating solution by the Opadry clarifier that 2.4kg is called as YS-1-19025.In the pan coating machine, be sprayed onto settled solution on the dry tablet agent and, used about 1.5mg on every side up to every.
Behind the painted and clarification coating, with the water base black ink of Opacode that is called as NS-78-17715 HM16 is imprinted on every on.On the inclined-plane printer, print.
Embodiment 5: research in the body
Carry out the research of Phase I, alcohol is to the hydromorphone tablet medicine effect of kinetics of embodiment 3 under assessment health volunteer's fasting and the feed situation.
What participate in the research is two groups of 24 health, the men and women that grows up, and in age 21-45 year (containing), body weight is 70kg and in the fluctuation 25% of the determined normal type of the height bodily form at least.In two groups of experimenters, research is single center, single agent, open labelling, four processing, four periods, four kinds of researchs that order is intersected.
In the group 1, below accepting under fasting state, each experimenter handles:
Handle hydromorphone tablet and the 240mL orange juice of A-16mg embodiment 3
The hydromorphone tablet of treatments B-16mg embodiment 3 and 240mL contain the orange juice of 4%v/v alcohol
Handle the hydromorphone tablet of C-16mg embodiment 3 and the orange juice that 240mL contains 20%v/v alcohol
Handle the hydromorphone tablet of D-16mg embodiment 3 and the orange juice that 240mL contains 40%v/v alcohol
In the group 2, each experimenter is normal early to be handled below the acceptance after the meal:
Handle hydromorphone tablet and the 240mL orange juice of E-16mg embodiment 3
Handle the hydromorphone tablet of F-16mg embodiment 3 and the orange juice that 240mL contains 4%v/v alcohol
Handle the hydromorphone tablet of G-16mg embodiment 3 and the orange juice that 240mL contains 20%v/v alcohol
Handle the hydromorphone tablet of H-16mg embodiment 3 and the orange juice that 240mL contains 40%v/v alcohol
Alcohol among treatments B, C, D, F, G and the H dilutes with orange juice, finishes off in about 30 minutes usually and does not drink without a break.To each processing, from medication about 14 hours before, the experimenter accepted the naltrexone of about 50mg as opioid antagonists, every day twice during the medication, continued about 48 hours after the medication.Have an appointment between the processing phase removing phase of 6 to 14 days, about 24 hours begin the removing phase after the medication.
During each the processing, about 0 (before medication) after medication, 2,4,6,8,10,12,16,20,24,27,30,36,42 and 48 hours collected blood sample from each experimenter, measurement blood plasma hydromorphone concentration.
Develop gauged liquid chromatography-mass spectrography logotype (LC/MS/MS) methods analyst plasma sample with CEDRA company.Extract human plasma and the interior mark hydromorphone-D that contains hydromorphone with ethyl acetate/hexane solution
3, remove organic layer and also extract once more, then evaporation drying.Reconstruct extract, every five equilibrium are injected among SCIEX API 4000 LC/MS/MS that the HPLC post is housed.Detect cation with many reaction detection (MRM) pattern.
The effectively quantitative hydromorphone concentration of I of this method is 0.05ng/mL.In the valid period, by drawing analyte: internal reference is to known analyte concentration, the calibration curve of the analyte that draws.By using 1/ concentration
2, the linear weight decay algorithm, delineate out calibration curve with the peak area rate (PAR) of calibration criterion.It is linear that the calibration curve of hydromorphone is in 0.05 to 10.0ng/mL scope.
Determine following pharmacokinetic parameter based on blood plasma hydromorphone concentration:
The maximum observed plasma concentration of Cmax-
Time during the Tmax-Cmax
The apparent attenuation rate constant of k-, its logarithm value by the plasma concentration that the linear attenuation at latter end logarithm-in the linear minimizing stage transforms is assessed.
(t1/2) value apparent half-life of T1/2-, it can be regarded as 0.693/k.
AUCt-was from 0 hour plasma concentration time graph area down to the time t that can detect concentration at last, and it is then definite by linear trapezoid method.
AUCinf-is extrapolated to the AUC value at unlimited place, its can be regarded as AUCt and be extrapolated to unlimited place area and, it can be calculated divided by k by time t (Ct) concentration.
In fasting and feed group, on first time point of 2 hours after the medication, plasma concentration approaches the quantitative limit; Afterwards, in all 4 kinds of processing methods, plasma concentration slowly rises.Every group has some experimenters that some no concentration values (discarding) or low value that can't clinical interpretation handle are occurred; From analyze, exclude these low values experimenter.The Tmax median was between 12 to 16 hours.Under the fasting situation, the cmax value during 3 groups of alcohol are handled slightly is higher than the value in the 0% alcohol processing, and the ratio in 4,20 and 40% alcohol is handled is respectively 117,131 and 128%.Under the situation, blood plasma hydromorphone concentration curve is similar in 4 kinds of processing on the feed, causes the Cmax ratio lower with respect to the fasting situation.The Cmax ratio does not demonstrate the dependency of any and pure percentage ratio (handle with respect to 0% alcohol, 4,20 and 40% alcohol is respectively 114,114 and 110% in handling).
3 kinds of alcohol are handled with respect to the 0% pure AUC value of handling and all reached 80 to 125% bioequivalence in the confidence intervals in fasting and feed group.Fig. 8 shows the mean concentration curve after 4 kinds of administrations in the fasting situation (group 1) are handled.Table 3 has been summarized pharmacokinetic parameter.Mean concentration curve after handling in 4 kinds of groups in Fig. 9 demonstration group 2, wherein all are handled all in standard administration after the meal early.Table 4 has been summed up the PK parameter.
Average (SD) hydromorphone pharmacokinetic parameter of table 3-group 1 fasting
| 0 | 4 | 20 | 40% alcohol | |
| Cmax(ng/mL) | 1.37(0.32) | 1.56(0.39) | 1.90(0.66) | 1.89(0.85) |
| Tmax (h) [median (scope)] | 16(6-27) | 12(6-27) | 12(4-16) | 12(6-24) |
| T1/2(h) | 12.4(5.1) | 12.6(6.5) | 12.4(7.2) | 11.1(3.0) |
| AUCinf | 40.6(110) | 39.9(14.1) | 43.7(12.1) | 42.2(13.2) |
| Ratio-arithmetic average (scope) | ||||
| Cmax | Reference | 1.19(0.8-1.7) | 1.35(0.7-2.4) | 1.37(0.7-2.5) |
| Ratio-% geometric average (90%CI) | ||||
| Cmax | Reference | 11670(104.48-130.36) | 131.16(117.01-147.02) | 128.31(114.18-144.17) |
| AUCinf | Reference | 96.83(87.48-107.19) | 103.21(92.93-114.62) | 101.65(91.32-113.13) |
Average (SD) hydromorphone pharmacokinetic parameter of table 4-group 2 medications
| 0 | 4 | 20 | 40% alcohol | |
| Cmax(ng/mL) | 1.42(0.50) | 1.64(0.60) | 1.52(0.32) | 1.56(0.56) |
| Tmax (h) [median (scope)] | 16(6-27) | 12(8-24) | 12(6-24) | 16(6-27) |
| T1/2(h) | 11.6(5.1) | 11.6(4.9) | 10.4(3.9) | 10.8(4.8) |
| AUCinf | 37.1(8.6) | 36.7(10.5) | 36.6(9.7) | 34.8(11.9) |
| Ratio-arithmetic average (scope) | ||||
| Cmax | Reference | 1.20(0.7-1.8) | 1.20(0.8-1.9) | 1.14(0.6-2.0) |
| Ratio-% geometric average (90%CI) | ||||
| Cmax | Reference | 113.72(99.97-129.36) | 114.36(100.14-130.61) | 110.34(97.08-125.41) |
| AUCinf | Reference | 94.72(86.44-103.79) | 106.21(96.63-116.73) | 94.09(85.91-103.04) |
Embodiment 6: single ratio compares: alcohol research is studied repeated drug taking
Study bioequivalence with batch (batch A is to a batch B) that is evaluated at two different locations productions.The design that it is four periods, repeat to study wherein two batches of two different administrations constantly each, is removed between handling therebetween, thus characterize in the experimenter and between variable health volunteer's medication pharmacokinetics transmutability.
Generally according to embodiment 1 and 2 described method and technology, the medicine of batch A and batch B is made oral osmotic sustained release forms of the present invention.Each experimenter one of handles twice below accepting in the order four periods that random arrangement is determined:
Handle A: batch A, use Naltrexone Hydrochloride 50mg
Treatments B: batch B, use Naltrexone Hydrochloride 50mg
Administration Naltrexone Hydrochloride 50mg when preceding 12 hours of hydromorphone dosage form of the present invention administration and administration.If desired, behind the administration hydromorphone 12 and 24 hours, the other 50mg dosage naltrexone of administration again.The minimum seven days removing phase is arranged between the medication.
Hydromorphone concentration in the blood plasma in the blood sample of regularly collecting after the testing drug administration is determined the area (AUC0-72 and AUC0-inf) under Cmax, Tmax, final half-life (t1/2) and the concentration-time curve.
When each sampling, ten milliliters of venous blood samples are packed into to be contained in the sample tube of anticoagulant.Collect in 1 hour centrifugal sample and be stored in-40 degrees centigrade, until test.Each with 0 (before the medication) after the hydromorphone dosage form of the present invention, each medication of 2,4,6,8,10,12,16,20,24,36,42,48,56,64 and 72 hours during blood sampling.Gauged liquid chromatography-mass spectrography logotype (LC/MS/MS) methods analyst plasma sample with the exploitation of CEDRA company.
Cmax ratio in this repeat administration is represented the transmutability between individuality.In this research, for each individual assessment cmax value ratio (high value/low value) and with former embodiment in cmax value ratio (the pure processing of alcohol/nothing) make comparisons.Figure 10 and 11 represents group 1 among the embodiment 5 and 2 comparison respectively.As shown in these figures, have alcohol to there being the viewed Cmax ratio ranges of alcohol processing identical ratio ranges not to be arranged, it represents transmutability between individuality.
Embodiment 7: sclerosing agent and acrylic resin are in the water and the research of the influence that oxycodone discharges in 40/60 (% volume) ethanol/water
Every kind of preparation that 10 grams are with or without stearyl alcohol prepares by the wet granulation technology.Get oxycodone hydrochloride, lactose and the Eudragit RS PO of aequum, be mixed in the suitable containers and mixed 5 minutes.Water to the pulverulent mixture pelletize until producing wet piece.Then wet piece is passed through the sieve of 16 mesh sizes, and under appropraite condition, make it dried overnight.In small container, the stearyl alcohol with aequum in water-bath melts.The stearyl alcohol that keeps fusing adds the dried particles of aequum and mixes in water-bath, the complete coating of stearyl alcohol that is melted up to granule.From water-bath, take out mixture, make it under appropraite condition, to cool off, then by 16 mesh sieve sizing.Pulvis Talci and magnesium stearate are added in the coated granules and with suitable blender mixes.Use suitable tablet machine then,, granule is pressed into the 375mg tablet as Carver pressure device.For the granule of coating stearyl alcohol not, granule is pressed into the 300mg tablet.
| Table 5: the oxycodone hydrochloride 30mg tablet formulation that stearyl alcohol is arranged | |
| Dosage=30mg/ sheet; Sheet=375mg ea. | |
| Material | Wt％ |
| Oxycodone hydrochloride | 8.02 |
| Lactose | 56.72 |
| Eudragit RS PO | 11.97 |
| Stearyl alcohol | 20.29 |
| Pulvis Talci | 1.99 |
| Magnesium stearate | 1.00 |
| Table 6: the oxycodone hydrochloride 30mg tablet formulation of no stearyl alcohol | |
| Dosage=30mg/ sheet; Sheet=300mg ea. | |
| Material | Wt％ |
| Oxycodone hydrochloride | 10.09 |
| Lactose | 71.13 |
| Eudragit RS PO | 14.99 |
| Pulvis Talci | 2.49 |
| Magnesium stearate | 1.30 |
Embodiment 8: the dihydromorphinone hydrochloride tablet formulation that has or do not have stearyl alcohol
With the production method identical, wherein replace oxycodone hydrochloride with dihydromorphinone hydrochloride with embodiment 7.
| Table 7: the dihydromorphinone hydrochloride 30mg tablet formulation that stearyl alcohol is arranged | |
| Dosage=30mg/ sheet; Sheet=375mg ea. | |
| Material | Wt％ |
| Oxycodone hydrochloride | 8.02 |
| Lactose | 56.72 |
| Eudragit RS PO | 11.97 |
| Stearyl alcohol | 20.29 |
| Pulvis Talci | 1.99 |
| Magnesium stearate | 1.00 |
| Table 8: the dihydromorphinone hydrochloride 30mg tablet formulation of no stearyl alcohol | |
| Dosage=30mg/ sheet; Sheet=300mg ea. | |
| Material | Wt％ |
| Oxycodone hydrochloride | 10.09 |
| Lactose | 71.13 |
| Eudragit RS PO | 14.99 |
| Pulvis Talci | 2.49 |
| Magnesium stearate | 1.30 |
Embodiment 9: the release function that has or do not have the opioid in the preparation of stearyl alcohol
The sample of this test is from embodiment 7 and 8.Tablet is tested release by USP VII type.Used release medium is as follows: the ethanol data: ethanol=40%EtOH/ water=0-4 hour, and water=4-24 hour then; The water number certificate: water is as all media at interval.(LAR007411, AAM1.773v1 AAM1.585v50) carry out drug test by the HPLC method in the assay laboratory.
The result: shown in Figure 12 and 13, stearyl alcohol has weakened the influence of ethanol to the opioid function.
Embodiment 10:Eudragit RS PO is to the influence of opioid function
Then use with the identical wet granulation method that embodiment 1 is described in detail and granulate., dispense Eudragit RS PO in the pulverulent mixture.The adjusting tablet weight has the 30mg opioid in making every.Preparation is shown in table 9 and 10.
| Table 9: the oxycodone hydrochloride 25mg tablet formulation of no Eudragit RS | |
| Dosage=25mg/ sheet; Sheet=310mg ea. | |
| Material | Wt％ |
| Oxycodone hydrochloride | 8.05 |
| Lactose | 69.04 |
| Stearyl alcohol | 19.92 |
| Pulvis Talci | 1.99 |
| Magnesium stearate | 1.00 |
| Table 10: the dihydromorphinone hydrochloride 25mg tablet formulation of no Eudragit RS | |
| Dosage=25mg/ sheet; Sheet=310mg ea. | |
| Material | Wt％ |
| Oxycodone hydrochloride | 7.99 |
| Lactose | 69.03 |
| Stearyl alcohol | 19.98 |
| Pulvis Talci | 2.00 |
| Magnesium stearate | 1.00 |
The result: as shown in figure 14, lacking Eudragit RS PO in the preparation does not have influence to the oxycodone hydrochloride function in the water or in water/ethanol medium.As shown in figure 15, lack Eudragit RS PO in the preparation dihydromorphinone hydrochloride function in the water or in water/ethanol medium is not had influence.
Embodiment 11: stearyl alcohol, hydrogenant polyoxy 60 Oleum Ricini and the relative influence of Brazil wax to the oxycodone hydrochloride function
Then use with the identical wet granulation method that embodiment 7 is described in detail and granulate., stearyl alcohol replaces with hydrogenant polyoxy 60 Oleum Ricini or Brazil wax.Tablet weight remains on 375mg has the 30mg opioid in making every.Preparation is as shown in table 11.Tablet discharges in following medium: the ethanol data: 40%EtOH/ water=0-4 hour, water=4-24 hour, the water number certificate: water was as all media at interval.
| Table 11: oxycodone hydrochloride 30mg tablet formulation | |||
| Total amount % | |||
| Material | Stearyl alcohol | Hydrogenant polyoxy Oleum Ricini | Brazil wax |
| Oxycodone hydrochloride | 8.02 | 8.06 | 8.08 |
| Lactose | 56.72 | 57.00 | 57.13 |
| Eudragit RS PO | 11.97 | 12.03 | 12.06 |
| Hard ester alcohol | 20.29 | 19.92 | 19.76 |
| Pulvis Talci | 1.99 | 1.98 | 1.98 |
| Magnesium stearate | 1.00 | 0.99 | 0.99 |
The result: as shown in figure 16, Brazil wax can be used for replacing stearyl alcohol, rather than hydrogenant polyoxy Oleum Ricini.
Embodiment 12: test OxyContin dosage form
Substantially under the following conditions carry out the test of OxyContin dosage form dissolution in vitro:
Dissolution conditions:
Equipment: USPII type
Mixing speed: 50rpm
Volume: 900mL
Bath temperature: 37 ± 0.5 ℃
Sample volume: 5ml
Dissolve medium: the water and 40% ethanol (every medium n=6 sheet) that are AG respectively
Sampling interval: T=0.5,1,2,4,6,8,10 and 12 hour
Detect with C18 post analytic sample solution and at the 286nm wavelength UV of place.Carry out quantitatively with sampling concentration with the linearity curve in the 1.05-100.53 μ g/mL scope.The concrete HPLC condition of this particular analysis is as follows substantially:
The HPLC condition:
Post: ZorbaxExtended C18,5 μ, 50 * 4.6mm
Mobile phase: THF: acetonitrile: the 34mM phosphate buffer (3: 25: 72, v/v/v)
Flow velocity: 1.2mL/ minute
Detector wavelength: 286nm
Volume injected: 30 μ L
Column temperature: 50 degrees centigrade
Running time: 4 minutes
The result as shown in figure 17.
Embodiment 13:16mg hydromorphone substrate
100 gram mixture, it contains 6g dihydromorphinone hydrochloride, 25gHPMCK100M, 15gHPMCK3,5g PVP K29-32,2g magnesium stearate and 47g microcrystalline Cellulose, this mixture dry mixed 3 minutes in rotation mill.The 267mg sample of weighing, then on Carver pressure device with 11/32 " standard round instrument and 1/2 ton of pressure compression, postpone the tablet that discharges thereby produce.
Embodiment 14:40mg oxycodone substrate
100 gram mixture, it contains 15g oxycodone hydrochloride, 25gHPMC K100M, 15gHPMCK3,5g PVP K29-32,2g magnesium stearate and 38g microcrystalline Cellulose, this mixture dry mixed 3 minutes in rotation mill.The 267mg sample of weighing, then on Carver pressure device with 11/32 " standard round instrument and 1/2 ton of pressure compression, postpone the tablet that discharges thereby produce.
Embodiment 15:90mg morphine sulfate substrate
100 gram mixture, it contains 18g morphine sulfate, 25gHPMCK100M, 15gHPMCK3,5gPVP K29-32,2g magnesium stearate and 40g microcrystalline Cellulose, this mixture dry mixed 3 minutes in rotation mill.The 500mg sample of weighing, then on Carver pressure device with 13/32 " standard round instrument and 3/4 ton of pressure compression, postpone the tablet that discharges thereby produce.
Embodiment 16:40mg oxymorphone HCl substrate
100 gram mixture, it contains 15g oxymorphone HCl, 25gHPMCK100M, 15gHPMCK3,5g PVP K29-32,2g magnesium stearate and 38g microcrystalline Cellulose, this mixture dry mixed 3 minutes in rotation mill.The 267mg sample of weighing, then on Carver pressure device with 11/32 " standard round instrument and 1/2 ton of pressure compression, postpone the tablet that discharges thereby produce.
Embodiment 17:40mg acid hydrocodone tartrate substrate
100 gram mixture, it contains 15g acid hydrocodone tartrate, 25gHPMC K100M, 15gHPMCK3,5g PVP K29-32,2g magnesium stearate and 38g microcrystalline Cellulose, this mixture dry mixed 3 minutes in rotation mill.The 267mg sample of weighing, then on Carver pressure device with 11/32 " standard round instrument and 1/2 ton of pressure compression, postpone the tablet that discharges thereby produce.
Embodiment 18:OROS oxycodone 40mg system
At first, come pharmaceutical compositions by the following material of dry mixed: 135.6g poly(ethylene oxide) N-150,54g oxycodone hydrochloride and 8g polyvidone (polyvinylpyrrolidone).In the Auxiliary Track formula blender of kitchen, mix, slowly add 70g ethanol.The wet granular that produces launches in pan by the box sieve sizing of 16 mesh, and is dry in the air at room temperature, then by the box sieve secondary of 16 mesh sizing.At last, material is reinstalled blender and sneak into the 0.5g magnesium stearate and mixed 1 minute.
Then, prepare the propelling compositions by the following material of dry mixed in the Auxiliary Track formula blender of kitchen: the 147.5g mean molecule quantity is poly(ethylene oxide), 40g sodium chloride powder, 8g 30 POVIDONE K 30 BP/USP 29-32 and the green ferrum oxide of 2g of 7000K.During mixing, slowly add 100g ethanol.The wet granular that produces launches in pan by the box sieve sizing of 16 mesh, and is dry in the air at room temperature, then by the box sieve secondary of 16 mesh sizing.At last, material is placed blender and sneak into the 0.5g magnesium stearate and mixed 1 minute.
Then, oxycodone compositions and propelling compositions are compressed into the two-layer core core.At first, 148mg oxycodone compositions is joined in the mold cavity and compression in advance, adds 123mg then and advance compositions and this lamination is advanced diameter 11/32 ", standard concave, in the dual layer arrangement.
Dual layer arrangement is with semi-transparent wall coating.Wall forms material and contains 99% and be called as 398-10's and cellulose acetate and 1% with 39.8% average acetyl content is called as Polyethylene Glycol 3350 and that have 3350 mean molecule quantities.Wall forms material and is dissolved in the mixture of 96% acetone and 4% water, makes 6% solid solution.Wall being formed material in pan coating machine is sprayed on the dual layer arrangement and, has used about 43mg film up to every on every side.
Pass the exit passageway that semi-transparent wall gets out a 1.0mm, make medicine layer and agent system external communications.Under 45 ℃ and 45% relative humidity dry 72 hours to remove remaining solvent.After the drying, dry tablet is 4 hours under 45 ℃ and suitable humidity.
Embodiment 19:90mg OROS morphine sulfate
At first, come pharmaceutical compositions by the following material of dry mixed: 135.6g poly(ethylene oxide) N-80,54g morphine sulfate and 8g polyvidone (polyvinylpyrrolidone).In the Auxiliary Track formula blender of kitchen, mix, slowly add 70g ethanol.The wet granular that produces launches in pan by the box sieve sizing of 16 mesh, and is dry in the air at room temperature, then by the box sieve secondary of 16 mesh sizing.At last, material is reinstalled blender and sneak into the 0.5g magnesium stearate and mixed 1 minute.
Then, prepare the propelling compositions by the following material of dry mixed in the Auxiliary Track formula blender of kitchen: the 147.5g mean molecule quantity is poly(ethylene oxide), 40g sodium chloride powder, 8g 30 POVIDONE K 30 BP/USP 29-32 and the green ferrum oxide of 2g of 7000K.During mixing, slowly add 100g ethanol.The wet granular that produces launches in pan by the box sieve sizing of 16 mesh, and is dry in the air at room temperature, then by the box sieve secondary of 16 mesh sizing.At last, material is placed blender and sneak into the 0.5g magnesium stearate and mixed 1 minute.
Then, morphine sulfate compositions and propelling compositions are compressed into the two-layer core core.At first, 333mg morphine sulfate compositions is joined in the mold cavity and compression in advance, adds 280mg then and advance compositions and this lamination is advanced diameter 7/16 ", standard concave, in the dual layer arrangement.
Dual layer arrangement is with semi-transparent wall coating.Wall forms material and contains 95% and be called as 398-10's and cellulose acetate and 5% with 39.8% average acetyl content is called as Polyethylene Glycol 3350 and that have 3350 mean molecule quantities.Wall forms material and is dissolved in the mixture of 96% acetone and 4% water, makes 6% solid solution.Wall being formed material in pan coating machine is sprayed on the dual layer arrangement and, has used about 33mg film up to every on every side.
Pass the exit passageway that semi-transparent wall gets out a 1.0mm, make medicine layer and agent system external communications.Under 45 ℃ and 45% relative humidity dry 72 hours to remove remaining solution.After the drying, dry tablet is 4 hours under 45 ℃ and suitable humidity.
Embodiment 20:40mg OROS hydrochloric acid oxymorphone
At first, come pharmaceutical compositions by the following material of dry mixed: 135.6g poly(ethylene oxide) N-80,54g hydrochloric acid oxymorphone and 8g polyvidone (polyvinylpyrrolidone).In the Auxiliary Track formula blender of kitchen, mix, slowly add 70g ethanol.The wet granular that produces moves in the pan by the box sieve series grain of 16 mesh, and is dry in the air at room temperature, granulates by the box sieve secondary of 16 mesh then.At last, material is reinstalled blender and sneak into the 0.5g magnesium stearate and mixed 1 minute.
Then, prepare the propelling compositions by the following material of dry mixed in the Auxiliary Track formula blender of kitchen: the 147.5g mean molecule quantity is poly(ethylene oxide), 40g sodium chloride powder, 8g 30 POVIDONE K 30 BP/USP 29-32 and the green ferrum oxide of 2g of 7000K.During mixing, slowly add 100g ethanol.The wet granular that produces launches in pan by the box sieve sizing of 16 mesh, and is dry in the air at room temperature, then by the box sieve secondary of 16 mesh sizing.At last, material is placed blender and sneak into the 0.5g magnesium stearate and mixed 1 minute.
Then, hydrochloric acid oxymorphone compositions and propelling compositions are compressed into the two-layer core core.At first, 148mg oxymorphone compositions is joined in the mold cavity and compression in advance, adds 123mg then and advance compositions and this lamination is advanced diameter 11/32 ", standard concave, in the dual layer arrangement.
Dual layer arrangement is with semi-transparent wall coating.Wall forms material and contains 99% and be called as 398-10's and cellulose acetate and 1% with 39.8% average acetyl content is called as Polyethylene Glycol 3350 and that have 3350 mean molecule quantities.Wall forms material and is dissolved in the mixture of 96% acetone and 4% water, makes 6% solid solution.Wall being formed material in pan coating machine is sprayed on the dual layer arrangement and, has used about 43mg film up to every on every side.
Pass the exit passageway that semi-transparent wall gets out a 1.0mm, make medicine layer and agent system external communications.Under 45 ℃ and 45% relative humidity dry 72 hours to remove remaining solution.After the drying, dry tablet is 4 hours under 45 ℃ and suitable humidity.
Embodiment 21:40mg OROS acid hydrocodone tartrate
At first, come pharmaceutical compositions by the following material of dry mixed: 135.6g poly(ethylene oxide) N-80,54g acid hydrocodone tartrate and 8g polyvidone (polyvinylpyrrolidone).In the Auxiliary Track formula blender of kitchen, mix, slowly add 70g ethanol.The wet granular that produces launches in pan by the box sieve sizing of 16 mesh, and is dry in the air at room temperature, then by the box sieve secondary of 16 mesh sizing.At last, material is reinstalled blender and sneak into the 0.5g magnesium stearate and mixed 1 minute.
Then, prepare the propelling compositions by the following material of dry mixed in the Auxiliary Track formula blender of kitchen: the 147.5g mean molecule quantity is poly(ethylene oxide), 40g sodium chloride powder, 8g 30 POVIDONE K 30 BP/USP 29-32 and the green ferrum oxide of 2g of 7000K.During mixing, slowly add 100g ethanol.The wet granular that produces launches in pan by the box sieve sizing of 16 mesh, and is dry in the air at room temperature, then by the box sieve secondary of 16 mesh sizing.At last, material is placed blender and sneak into the 0.5g magnesium stearate and mixed 1 minute.
Then, acid hydrocodone tartrate compositions and propelling compositions are compressed into the two-layer core core.At first, 148mg acid hydrocodone tartrate compositions is joined in the mold cavity and compression in advance, adds 123mg then and advance compositions and this lamination is advanced diameter 11/32 ", standard concave, in the dual layer arrangement.
Dual layer arrangement is with semi-transparent wall coating.Wall forms material and contains 99% and be called as 398-10's and cellulose acetate and 1% with 39.8% average acetyl content is called as Polyethylene Glycol 3350 and that have 3350 mean molecule quantities.Wall forms material and is dissolved in the mixture of 96% acetone and 4% water, makes 6% solid solution.Wall being formed material in pan coating machine is sprayed on the dual layer arrangement and, has used about 43mg film up to every on every side.
Pass the exit passageway that semi-transparent wall gets out a 1.0mm, make medicine layer and agent system external communications.Under 45 ℃ and 45% relative humidity dry 72 hours to remove remaining solution.After the drying, dry tablet is 4 hours under 45 ℃ and suitable humidity.
Claims (71)
1. continue the liberation port oral dosage form, it contains opioid and continues to discharge the dosage structure, wherein exist under the situation of alcohol-water solution, described lasting release dosage structure discharges described opioid from described sustained release forms, wherein alcohol-water solution contains the alcohol that is equal to or greater than about 20% volume/volume concentration, and wherein, the ratio that coexists between the maximum blood plasma opioid of the average single agent concentration that is reached when described opioid sustained release forms is got along well described alcohol-water solution administering drug combinations in the maximum blood plasma opioid of the average single agent concentration that described opioid sustained release forms and described alcohol-water solution are reached during to patient's administering drug combinations is equal to or less than about 1.8: 1.
2. according to the lasting liberation port oral dosage form of claim 1, wherein said ratio is equal to or less than about 1.6: 1, preferably is equal to or less than about 1.4: 1.
3. continue the liberation port oral dosage form, it contains opioid and continues to discharge the dosage structure, wherein exist under the situation of alcohol-water solution, described lasting release dosage structure discharges described opioid from described sustained release forms, wherein alcohol-water solution contains the alcohol that is equal to or greater than about 20% volume/volume concentration, and wherein, the ratio between the maximum blood plasma opioid of the single patient list agent concentration that is reached when the maximum blood plasma opioid of the single patient list agent concentration that described opioid sustained release forms and alcohol-water solution are reached during to patient's administering drug combinations coexists described opioid sustained release forms discord alcohol-water solution administering drug combinations is equal to or less than about 5: 1.
4. according to the lasting liberation port oral dosage form of claim 3, wherein said ratio is equal to or less than about 4: 1, preferably is equal to or less than about 3: 1.
5, continue the liberation port oral dosage form, it contains opioid and continues to discharge the dosage structure, wherein exist under the situation of alcohol-water solution, described lasting release dosage structure discharges described opioid from described sustained release forms, wherein alcohol-water solution contains the alcohol that is equal to or greater than about 20% volume/volume concentration, and wherein, described opioid sustained release forms discharges the opioid dosage that is less than or equal to about 80 percentage by weights from described opioid sustained release forms, it records as follows: (a) utilize to contain the testing in vitro method of tested media with (b) in initial back about 2 hours of testing in vitro method; And wherein, described tested media contains the alcohol-water solution that is equal to or greater than about 20% volume/volume concentration.
6. according to the lasting liberation port oral dosage form of claim 5, wherein said release is less than or equal to the opioid dosage of about 50 percentage by weights, preferably is less than or equal to the opioid dosage of about 25 percentage by weights.
7. continue the liberation port oral dosage form, it contains opioid and continues to discharge the dosage structure, wherein exist under the situation of alcohol-water solution, described lasting release dosage structure discharges described opioid from described sustained release forms, wherein alcohol-water solution contains the alcohol that is equal to or greater than about 20% volume/volume concentration, and wherein, the ratio that coexists between the time median of the maximal plasma concentration that reached when described sustained release forms is got along well described alcohol-water solution administering drug combinations at the time median of single agent maximal plasma concentration that described opioid sustained release forms and described alcohol-water solution are reached during to patient's administering drug combinations is about 0.5 to about 1.0.
8. according to arbitrary lasting liberation port oral dosage form of claim 1 to 7, it provides once a day or twice medication every day.
9. according to arbitrary lasting liberation port oral dosage form of claim 1 to 8, wherein said opioid is selected from morphine, codeine, dimethyl morphine, diacetylmorphine, oxycodone, hydrocodone, paracodin, hydromorphone, oxymorphone, Buddhist nun and restrains morphine, methadone, hydrochloric acid levothyl ethyl ester, Pethidine, ketobemidone, the third oxygen sweet smell, dextropropoxyphene, dextromoramide, bezitramide, pirinitramide, pentazocine, phenazocine and pharmaceutically acceptable salt thereof.
10. according to arbitrary lasting liberation port oral dosage form of claim 1 to 9, wherein said alcohol-water solution is equal to or greater than about 25% volume/volume, more preferably be equal to or greater than about 30% volume/volume, more preferably be equal to or greater than about 35% volume/volume, and most preferably be equal to or greater than about 40% volume/volume.
11. arbitrary lasting liberation port oral dosage form according to claim 1 to 10, it further contains opioid antagonists, as naltrexone levallorphan, naloxone, naltrexone, buprenorphine, nalbuphine, nalorphine, nalmefene, diprenorphine, cyclazocine, etazocine, metazocine or naloxone.
12. arbitrary lasting liberation port oral dosage form according to claim 1 to 11, the scope that wherein said peroral dosage form contains the amount of described opioid is that about 0.001mg is to about 5000mg, preferred about 0.01mg is to about 1000mg, more preferably from about 0.1mg is to about 750mg, more preferably from about 0.5mg is to about 500mg, even more preferably from about 0.5mg to about 250mg, even more preferably from about 1mg to about 100mg, and 1mg about 50mg extremely most preferably from about.
13. according to arbitrary lasting liberation port oral dosage form of claim 1 to 12, wherein said peroral dosage form is selected from disperse system, dissolution system, dispersed/dissolved combined system, ion exchange resin system, osmosis system, gastric retention dosage form, continues microball preparation and infiltration sustained release forms.
14. according to the lasting liberation port oral dosage form of claim 13, wherein said disperse system is selected from bunkerage or substrate equipment.
15. according to the lasting liberation port oral dosage form of claim 13, wherein said dissolution system is selected from the capsule dissolves system, as sheet, ball and stromatolysis system after a little while.
16. according to the lasting liberation port oral dosage form of claim 13, wherein said osmotic dosage form comprise to small part by semi-transparent film formed cell.
17. according to the lasting liberation port oral dosage form of claim 16, wherein said semipermeable membrane polyvinyl alcohol film coating.
18. according to the lasting liberation port oral dosage form of claim 16 or 17, but it comprises the pharmaceutical composition of serosity, suspending agent or solution form, little outlet and extension layer.
19. according to the lasting liberation port oral dosage form of claim 18, wherein said medicine layer has sublayer or the annealing coating that is connected with semipermeable membrane.
20. according to arbitrary lasting liberation port oral dosage form of claim 16 to 19, wherein said infiltration sustained release forms comprises enteric coating or non-enteric coating.
21. according to the lasting liberation port oral dosage form of claim 20, wherein said enteric coating contains the material that is selected from CAP, HMPCP and PVAP.
22. lasting liberation port oral dosage form according to claim 13, it is the form of basic osmotic pumps dosage form, its contain surround and around semipermeable membrane and contain the inside cell of medicine layer, it contains described medicine and is mixed with one or more excipient, and described excipient is suitable for providing the osmotically active gradient and forms the compound formulation that can send by forming draw fluid.
23. according to the lasting liberation port oral dosage form of claim 22, wherein said excipient comprises suitable pharmaceutical carrier, binding agent, lubricant and penetrating agent.
24. according to the lasting liberation port oral dosage form of claim 22 or 23, wherein said semipermeable membrane contains the polymer that is selected from homopolymer and copolymer, as cellulose esters, cellulose ether and cellulose esters-ether.
25. according to arbitrary lasting liberation port oral dosage form of claim 22 to 24, it further contains flux-regulating agent, it especially is selected from polyhydroxy-alcohol, gathers the polyester of alkane glycol, polyene glycol, alkane glycol etc.
26. according to the lasting liberation port oral dosage form of claim 13, it is the form of infiltration sustained release forms, but it contains first medicine layer of osmotically active composition and contains than first medicine layer more second medicine layer, and the optional extension layer of multiple medicines thing.
27., demonstrate one or more osmopolymer of the molten relative small-molecular weight that expands when wherein the osmotically active composition is selected from penetrating agent such as salt with draw fluid according to the lasting liberation port oral dosage form of claim 26.
28. according to the lasting liberation port oral dosage form of claim 26 or 27, wherein first medicine layer further comprises excipient, as binding agent, lubricant, antioxidant and coloring agent.
29. according to arbitrary lasting liberation port oral dosage form of claim 26 to 28, wherein said second medicine layer contains opioid and is mixed with the excipient of the selection that is suitable for providing the osmotically active gradient, as suitable pharmaceutical carrier.
30. according to the lasting liberation port oral dosage form of claim 29, wherein second medicine layer does not have the osmotically active agent.
31. according to arbitrary lasting liberation port oral dosage form of claim 26 to 30, it further comprises outlet opening.
32. according to arbitrary lasting liberation port oral dosage form of claim 26 to 31, wherein first and second medicine layers further comprise the hydrophilic polymer carrier, especially corrosive carrier in the intestinal environment.
33. according to arbitrary lasting liberation port oral dosage form of claim 26 to 32, it further contains semipermeable membrane, especially cellulose ester, cellulose ether and cellulose esters-ether.
34. according to arbitrary lasting liberation port oral dosage form of claim 26 to 33, it further contains flux-regulating agent, especially flux enhancement agent or flow depressant, and it is selected from the polyester etc. of polyhydroxy-alcohol, poly-alkane glycol, polyene glycol, alkane glycol.
35. according to arbitrary lasting liberation port oral dosage form of claim 26 to 34, but wherein extension layer contains the water active layer of osmopolymer or penetrating agent.
36. according to the lasting liberation port oral dosage form of claim 13, it is the form of soft capsule or hard capsule.
37. according to the lasting liberation port oral dosage form of claim 36, its form be enclosed construction pharmaceutical preparation is encapsulated in wherein a lamellar body soft capsule.
38. according to the lasting liberation port oral dosage form of claim 36 or 37, but wherein said soft capsule coating has asymmetric water active layer as extension layer and outlet opening.
39. according to arbitrary lasting liberation port oral dosage form of claim 36 to 38, wherein said soft capsule further comprises barrier layer.
40. according to arbitrary lasting liberation port oral dosage form of claim 36 to 39, but wherein extension layer forms at the capsular discrete portions that not exclusively covers the barrier layer coating.
41. according to the lasting liberation port oral dosage form of claim 36, its form is served as reasons and is covered and main body two lamellar body hard capsules dimerous.
42. according to the lasting liberation port oral dosage form of claim 41, wherein said capsule is encapsulated as capsule with semi-transparent thin slice.
43. according to the lasting liberation port oral dosage form of claim 41 or 42, wherein said hard capsule is made near each part has coupling their open end lock ring, the main body after it can be integrated and pin eclipsed lid and inject preparation.
44. according to arbitrary lasting liberation port oral dosage form of claim 36 to 43, wherein said capsule further comprises semipermeable membrane.
45. according to the lasting liberation port oral dosage form of claim 44, wherein said semipermeable membrane contains flux-regulating agent.
46. according to arbitrary lasting liberation port oral dosage form of claim 43 to 45, wherein said semipermeable membrane surrounds and forms cell, described cell contains one layer or more, but one of them layer is an extension layer, preferably contains penetrating agent.
47. according to arbitrary lasting liberation port oral dosage form of claim 36 to 46, it further contains barrier layer, is preferably provided with plasticizer.
48. according to the lasting liberation port oral dosage form of claim 13, it is the form of cylindric substrate, it contains opioid, wherein, the substrate end is circular and protruding shape, and ribbon is around cylindric substrate, and described ribbon is formed by the material of water insoluble relatively solution environmental.
49. lasting liberation port oral dosage form according to claim 13, it is the form of gastric retention dosage form, comprise sheet or capsule, it contains the many granules of dispersion of the limited dissolved drug in the polymer hydrophilic, that watery distension is molten, crosslinked, and described polymer keeps its physical integrity but dissolving rapidly subsequently in the medicament duration.
50. according to the lasting liberation port oral dosage form of claim 13, it is the form of substrate dosage form, it contains glue composition, hydrophobic vehicle, medicine and diluent.
51. according to the lasting liberation port oral dosage form of claim 13, it is the form of infiltration ball, it contains the crystal seed that enough osmotically actives are arranged or other materials of superfine quality, and it is with the coating thickness wide semipermeable membrane or not semi-transparent in the film coating of water that distributes.
52. wherein there is described infiltration ball in the lasting liberation port oral dosage form according to claim 51 in the capsule.
53. arbitrary lasting liberation port oral dosage form as medicine according to claim 1 to 52.
Be used to prepare application 54. continue the liberation port oral dosage form at described opioid sustained release forms and the alcohol-water solution medicine of treatment pain during to patient's administering drug combinations, described lasting liberation port oral dosage form contains opioid and the lasting release dosage structure that continues to discharge dosage is provided, and wherein alcohol-water solution contains the alcohol that is equal to or greater than about 20% volume/volume concentration; And from described lasting release opioid dosage form, discharge described opioid; Wherein, the ratio that coexists between the maximum blood plasma opioid of the average single agent concentration that is reached when described lasting release opioid peroral dosage form is got along well described alcohol-water solution administering drug combinations in the maximum blood plasma opioid of the average single agent concentration that described lasting release opioid peroral dosage form and alcohol-water solution are reached during to patient's administering drug combinations is equal to or less than about 1.8: 1.
55. according to the application of the lasting liberation port oral dosage form of claim 54, wherein said ratio is equal to or less than about 1.6: 1, preferably is equal to or less than about 1.4: 1.
56. continue the application that the liberation port oral dosage form is used to prepare the medicine of treatment pain when described opioid continues liberation port oral dosage form and alcohol-water solution to patient's administering drug combinations, described lasting liberation port oral dosage form contains opioid and the lasting release oral dose structure that continues to discharge dosage is provided; Wherein alcohol-water solution contains the alcohol that is equal to or greater than about 20% volume/volume concentration; And from described lasting release opioid peroral dosage form, discharge described opioid; Wherein, the ratio between the maximum blood plasma opioid of the single patient list agent concentration that is reached when the maximum blood plasma opioid of the single patient list agent concentration that described opioid sustained release forms and alcohol-water solution are reached during to patient's administering drug combinations coexists described opioid sustained release forms discord alcohol-water solution administering drug combinations is equal to or less than about 5: 1.
57. according to the application of the lasting liberation port oral dosage form of claim 56, wherein said ratio is equal to or less than about 4: 1, preferably is equal to or less than about 3: 1.
58, continue the application that the liberation port oral dosage form is used to prepare the medicine of treatment pain when described opioid continues liberation port oral dosage form and alcohol-water solution to patient's administering drug combinations, described lasting liberation port oral dosage form contains opioid and the lasting release oral dose structure that continues to discharge dosage is provided; Wherein alcohol-water solution contains the alcohol that is equal to or greater than about 20% volume/volume concentration; And from described lasting release opioid peroral dosage form, discharge described opioid; Wherein, described opioid sustained release forms discharges the opioid dosage that is less than or equal to about 80 percentage by weights from described opioid sustained release forms, it records as follows: (a) utilize to contain the testing in vitro method of tested media with (b) in initial back about 2 hours of testing in vitro method; And wherein, described tested media contains the alcohol-water solution that is equal to or greater than about 20% volume/volume concentration.
59. according to the application of the lasting liberation port oral dosage form of claim 58, the wherein said opioid dosage that is less than or equal to about 50 percentage by weights that is released to preferably is less than or equal to the opioid dosage of about 25 percentage by weights.
60. continue the application that the liberation port oral dosage form is used to prepare the medicine of treatment pain when described opioid continues liberation port oral dosage form and alcohol-water solution to patient's administering drug combinations, described lasting liberation port oral dosage form contains opioid and the lasting release oral dose structure that continues to discharge dosage is provided; Wherein alcohol-water solution contains the alcohol that is equal to or greater than about 20% volume/volume concentration; And from described lasting release opioid dosage form, discharge described opioid; Wherein, be about 0.5 to about 1.0 at the time median of single agent maximal plasma concentration that described opioid sustained release forms and described alcohol-water solution are reached during to the patient's administering drug combinations ratio that described opioid sustained release forms gets along well between the time median of single agent maximal plasma concentration of being reached when described alcohol-water solution is united to patient's administration that coexists.
61. according to the application of arbitrary lasting liberation port oral dosage form of claim 54 to 60, it provides once a day or twice medication every day.
62. according to the application of arbitrary lasting liberation port oral dosage form of claim 54 to 61, wherein said lasting release oral dose structure comprises the oral lasting release dosage structure of infiltration.
63. according to arbitrary application of claim 54 to 62, wherein said alcohol comprises ethanol.
64. arbitrary application according to claim 54 to 63, wherein said alcohol-water solution is equal to or greater than about 25% volume/volume, more preferably be equal to or greater than about 30% volume/volume, more preferably be equal to or greater than about 35% volume/volume, and most preferably be equal to or greater than about 40% volume/volume.
65. arbitrary application according to claim 54 to 64, the scope that wherein said peroral dosage form contains the amount of described opioid is that about 0.001mg is to about 5000mg, preferred about 0.01mg is to about 1000mg, more preferably from about 0.1mg is to about 750mg, more preferably from about 0.5mg is to about 500mg, even more preferably from about 0.5mg to about 250mg, even more preferably from about 1mg to about 100mg, and 1mg about 50mg extremely most preferably from about.
66. according to arbitrary application of claim 54 to 65, wherein said lasting release opioid peroral dosage form further contains the instantaneous relase composition that is used for the instantaneous relase opioid.
67. according to arbitrary application of claim 54 to 66, wherein said opioid is selected from morphine, codeine, dimethyl morphine, diacetylmorphine, oxycodone, hydrocodone, paracodin, hydromorphone, oxymorphone, Buddhist nun and restrains morphine, methadone, hydrochloric acid levothyl ethyl ester, Pethidine, ketobemidone, the third oxygen sweet smell, dextropropoxyphene, dextromoramide, bezitramide, pirinitramide, pentazocine, phenazocine and pharmaceutically acceptable salt thereof.
68. arbitrary application according to claim 54 to 67, wherein said lasting release opioid peroral dosage form further contains opioid antagonists, as naltrexone levallorphan, naloxone, naltrexone, buprenorphine, nalbuphine, nalorphine, nalmefene, diprenorphine, cyclazocine, etazocine, metazocine or naloxone.
69. according to arbitrary application of claim 54 to 68, wherein said administering drug combinations and described alcohol-water solution while or separate administration.
70. according to arbitrary application of claim 54 to 69, wherein said peroral dosage form is selected from disperse system, dissolution system, dispersed/dissolved combined system, ion exchange resin system, osmosis system, gastric retention dosage form, continues microball preparation and infiltration sustained release forms.
71. according to arbitrary lasting liberation port oral dosage form of claim 1 to 53 or according to arbitrary application of claim 54 to 70, wherein said opioid is selected from: dihydromorphinone hydrochloride, oxycodone hydrochloride, morphine sulfate, hydrochloric acid oxymorphone and acid hydrocodone tartrate.
Applications Claiming Priority (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US73199505P | 2005-10-31 | 2005-10-31 | |
| US60/731,995 | 2005-10-31 | ||
| US60/731995 | 2005-10-31 | ||
| US80201706P | 2006-05-18 | 2006-05-18 | |
| US60/802017 | 2006-05-18 | ||
| US60/802,017 | 2006-05-18 | ||
| US83704906P | 2006-08-11 | 2006-08-11 | |
| US60/837,049 | 2006-08-11 | ||
| US60/837049 | 2006-08-11 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1957909A true CN1957909A (en) | 2007-05-09 |
| CN1957909B CN1957909B (en) | 2013-09-11 |
Family
ID=38069863
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200610143171 Active CN1957909B (en) | 2005-10-31 | 2006-09-18 | Methods of reducing alcohol-induced dose dumping for opioid sustained release oral dosage forms |
| CNA2006800495440A Pending CN101351202A (en) | 2005-10-31 | 2006-10-31 | Methods of reducing alcohol-induced dose dumping for opioid sustained release oral dosage forms |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800495440A Pending CN101351202A (en) | 2005-10-31 | 2006-10-31 | Methods of reducing alcohol-induced dose dumping for opioid sustained release oral dosage forms |
Country Status (2)
| Country | Link |
|---|---|
| CN (2) | CN1957909B (en) |
| ZA (1) | ZA200804734B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104224737A (en) * | 2010-02-24 | 2014-12-24 | 硕腾有限责任公司 | Veterinary compositions |
| CN105287434A (en) * | 2009-03-18 | 2016-02-03 | 赢创罗姆有限公司 | Ethanol influence-resistant controlled-release medicine composition adopting coating containing neutral vinyl polymers and excipients |
| CN108309949A (en) * | 2018-03-15 | 2018-07-24 | 西南药业股份有限公司 | A kind of preparation method and products thereof of morphine osmotic pump tablet |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8626098D0 (en) * | 1986-10-31 | 1986-12-03 | Euro Celtique Sa | Controlled release hydromorphone composition |
| US5266331A (en) * | 1991-11-27 | 1993-11-30 | Euroceltique, S.A. | Controlled release oxycodone compositions |
| US5968551A (en) * | 1991-12-24 | 1999-10-19 | Purdue Pharma L.P. | Orally administrable opioid formulations having extended duration of effect |
| US5965161A (en) * | 1994-11-04 | 1999-10-12 | Euro-Celtique, S.A. | Extruded multi-particulates |
| DK1009387T3 (en) * | 1997-07-02 | 2006-08-14 | Euro Celtique Sa | Long-release stabilized tramadol formulations |
| US6228863B1 (en) * | 1997-12-22 | 2001-05-08 | Euro-Celtique S.A. | Method of preventing abuse of opioid dosage forms |
-
2006
- 2006-09-18 CN CN 200610143171 patent/CN1957909B/en active Active
- 2006-10-31 CN CNA2006800495440A patent/CN101351202A/en active Pending
-
2008
- 2008-05-30 ZA ZA200804734A patent/ZA200804734B/en unknown
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105287434A (en) * | 2009-03-18 | 2016-02-03 | 赢创罗姆有限公司 | Ethanol influence-resistant controlled-release medicine composition adopting coating containing neutral vinyl polymers and excipients |
| CN104224737A (en) * | 2010-02-24 | 2014-12-24 | 硕腾有限责任公司 | Veterinary compositions |
| CN108309949A (en) * | 2018-03-15 | 2018-07-24 | 西南药业股份有限公司 | A kind of preparation method and products thereof of morphine osmotic pump tablet |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101351202A (en) | 2009-01-21 |
| CN1957909B (en) | 2013-09-11 |
| ZA200804734B (en) | 2009-11-25 |
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