Patent
Opioid taper regimen
| العنوان: | Opioid taper regimen |
|---|---|
| Patent Number: | 11253,512 |
| تاريخ النشر: | February 22, 2022 |
| Appl. No: | 16/842079 |
| Application Filed: | April 07, 2020 |
| مستخلص: | A opioid taper regimen, and its method of manufacture, for use in a method of opioid reduction leading to abstinence. Said regimen is administered within the range of 2 to 4 years, or more. The regimen comprises novel approaches to common problems encountered during tapers of low dose opioid addiction. The reduction regimen is generally linear; reduces the dosage level once per week; doses every six hours; reduces doses by steps in the range of about 0.001 to 0.0500 mg; has, near the end, ten weeks of doses of about 0.0025 mg buprenorphine q.i.d.; followed by four or more weeks of placebos. Instructions for manufacture of doses that differ by 0.0025 mg and 0.0050 mg buprenorphine are specified. |
| Inventors: | Grossman, Joseph Leon (Boulder, CO, US) |
| Claim: | 1. A method of dividing and linearly tapering doses and administering opioids, comprising: providing patients with a medication with doses specifically intended, designed, and made to be consumed orally, a tablet or a film, for the purpose of treating individuals addicted to or dependent upon opioids, or diagnosed with opioid use disorder, for the purpose of reducing said individuals' opioid consumption to zero, between two and eight doses of buprenorphine opioid, at intervals of three to twenty-four hours, inclusive, administering said opioid, for an initial period of four or more weeks, a daily dose of between one and eight milligrams, at a constant dose; following said initial period with a second period of opioid administration with a duration of between 100 to 900 weeks, wherein a linear reduction once each week of the daily dose of said opioid in the range of a reduction from 0.002 to 0.030 milligrams per week, with administration continuing in divided doses between one time and eight times per day; following said second period of 100 to 900 weeks with a third time period having a duration of from five and 15 weeks, wherein a daily dosage of said opioid in the range of 0.0005 milligrams to 0.0200 milligrams per day, at the same dosage every day through entirety of period 3, is administered in divided doses from two to eight times per day; following said third period of five to 15 weeks with a fourth time period with a duration from four to eight weeks, wherein said daily dosage is a placebo containing zero milligrams of said opioid, administered four, three, two and one time(s) per day, each dose configuration of four, three, two or one time(s) per day to have a duration of at least one week. |
| Claim: | 2. A method of claim 1 of administering buprenorphine comprising: providing patients with a medication with doses specifically intended, designed, and made to be consumed orally, a tablet or a film, for the purpose of treating individuals addicted to or dependent upon opioids, or diagnosed with opioid use disorder, for the purpose of reducing said individuals' opioid consumption to zero, for an initial time period of four weeks, a daily dose of 2 mg/day total in four divided doses of 0.500 mg, four times per day, all daily total dosing being administered in four divided doses at six-hour intervals, throughout; administering, following said initial period with a second period, that being of 100 weeks duration, of buprenorphine wherein the linear reduction of buprenorphine is a 0.02 (two one-hundredths) milligrams reduction per week, of the daily dose; administering, following the said second period of 100 weeks, during a third time period having a duration of ten weeks, wherein a daily dosage of said opioid of 0.01 (one one-hundredth) mg/day in four divided doses per day of 0.0025 (twenty-five thousandths) milligrams; administering, following said third period with a fourth time period with a duration of four weeks, wherein said total daily dosage of opioid is zero mg and doses consist of doses identical in appearance, protocol and packaging to all previous active doses, with the exception that in the first of the final four weeks there are four inert doses per day, in the second of the four weeks there are three inert doses a day, in the third week being two inert doses a day, and in the final week of the taper regimen, there being one inert dose per day, doses during these four weeks being dispensed at six, eight, twelve and twenty-four hour intervals for the successive weeks respectively, with total administration being part of a taper regimen of 118 weeks. |
| Claim: | 3. A method of claim 1 of administering buprenorphine in a 218-week taper regimen, comprising: providing patients with a medication with doses specifically intended, designed, and made to be consumed orally, a tablet or a film, for the purpose of treating individuals addicted to or dependent upon opioids, or diagnosed with opioid use disorder, for the purpose of reducing said individuals' opioid consumption to zero, for an initial time period of four weeks, a daily dose of 2 mg/day total in four divided doses of 0.500 mg, four times per day, all daily total dosing being administered in four divided doses at six-hour intervals, throughout; administering, following said initial period with a second period, that being of 200 weeks duration, of buprenorphine, wherein the linear reduction of buprenorphine is a 0.01 (one one-hundredth) milligram reduction per week, of the daily dose, which is administered in four divided doses; administering, following the said second period of 200 weeks, during a third time period having a duration of ten weeks, wherein a daily dosage of said opioid of 0.01 (one one-hundredth) mg/day in four divided doses per day of 0.0025 (twenty-five thousandths) milligrams; administering, following said third period with a fourth time period with a duration of four weeks, wherein said total daily dosage of opioid is zero mg and doses consist of doses and dosing identical in appearance, protocol and packaging to all previous active doses, with the exception that in the first of the final four weeks there are four inert doses per day, in the second of the four weeks there are three inert doses a day, in the third week being two inert doses a day, and in the final week of the taper regimen, there being one inert dose per day, doses during these four weeks being dispensed at six, eight, twelve and twenty-four hour intervals for the successive weeks respectively, with total administration being part of a taper regimen of 218 weeks. |
| Claim: | 4. A method of manufacturing a taper regimen of opioid medication, said taper regimen comprising: starting with manufacture of a dose of medication in the range of one to eight milligrams (mg), intended for the initial period of four weeks or more, during which time this is the daily per day total, manufactured to be administered as four divided doses; manufacturing the medication for a range of 100 to 900 weeks, during said weeks the dose of opioid being reduced weekly in the range of 0.01 (one one-hundredth) to 0.03 (three one-hundredths) mg opioid; manufacturing medication for administration during the period following 100 to 900 weeks, of five to fifteen weeks duration, being a dose of 0.01 (one one-hundredth) mg opioid, manufactured as four divided doses of 0.0025 mg opioid, and; manufacturing medication to follow the five to fifteen weeks of 0.01 mg opioid total per day, by one to ten weeks of doubly unblinded inert doses, this final sequence completing any specific said taper regimen; wherein said manufacturing includes the steps of: mixing to complete homogeneity 103 (one hundred and three) kilograms of a mixture consisting of 0.515 kilograms of buprenorphine, and 102.485 (one hundred and two point four eight five) kilograms, inert filler/binder/diluent; removing 4.000 (four) kilograms of the 103 kg mixture (leaving 99 kg) with said 103 kg consisting of 0.5% active ingredient buprenorphine and 99.5% inactive mixture; processing the 4.000 (four) kilograms that are removed, to manufacture 40,000 doses/tablets (minus normal manufacturing loss due to equipment adhesion or other cause) of 100 mg, each dose/tablet containing 0.500 mg of buprenorphine; adding precisely one kilogram of the inert components: filler, binder, diluent to the above mass of 99 kilograms (kg) (the 103 kg mass above minus 4 kg removed) to reconstitute to 100 kg; maintaining consistent moisture content through quantitative assay; replicating the above protocol by performing 99 (ninety-nine) additional actions of continuing the portion-removal/reconstitution method, at each step removing 1 (one) kg of mixture of active/inactive mixture for processing into tablets/doses and then reconstituting the batch, with one kg of inert binder/filler/diluent, to 100 kg; processing at each step the removed one kg of compound into 10,000 doses, or multiples thereof; continuing the portion-removal/reconstitutions, through the 100th portion-removal/reconstitution, with the dose being produced in the 100th step containing 0.005 (five one-thousandths) mg per 100 (hundred) mg tablet/dose; adding 101 (one hundred and one) kg, immediately following the 100th portion-removal, of inert mixture; mixing the resultant 200 (two hundred) kg mass to homogeneity, wherein said 200 kg batch is processed into doses of 100 mg that each contains 0.0025 (twenty-five ten-thousandths) mg of buprenorphine per 100 mg dose; removing 10 (ten) kg of said 200 kg of mixture to produce a number of doses equal to ten times the number of each previous week thereby providing ten weeks of a 0.0025 mg/100 mg dose, and; utilizing whatever portion of the remaining 190 kg of mixture is required for the final ten weeks of other regimens. |
| Claim: | 5. A method of manufacture of claim 4 , of a taper regimen of doses of buprenorphine, with 98% of the reduction steps being in a linear fashion, with a duration of 118 weeks, wherein the manufactured product incorporates the following dosing requirements of starting at 0.5 (one-half) mg of buprenorphine, reducing manufactured doses in increments of 0.005 (five one-thousandths) mg of buprenorphine, and producing also doses of 0.0025 (twenty-five one-thousandths) mg of buprenorphine, comprising: mixing to complete homogeneity 103 (one hundred and three) kilograms of a mixture consisting of 0.515 kilograms of buprenorphine, and 102.485 (one hundred and two point four eight five) kilograms of pharmacologically inert filler/binder/diluent; removing 4.000 (four) kilograms of the 103 kg mixture (leaving 99 kg) with said 103 kg consisting of 0.5% active ingredient buprenorphine and 99.5% inactive mixture; processing the 4.000 (four) kilograms that are removed, to manufacture 40,000 doses/tablets of 100 mg, each dose/tablet containing 0.500 mg of buprenorphine; adding precisely one kilogram of the inert components: filler, binder, diluent to the above mass of 99 kilograms (kg) (the 103 kg mass above minus 4 kg removed) to reconstitute to 100 kg; maintaining consistent moisture content through quantitative assay; replicating the above protocol by performing 99 (ninety-nine) additional actions of continuing the portion-removal/reconstitution method, at each step removing 1 (one) kg of mixture of active/inactive mixture for processing into tablets/doses and then reconstituting the batch, with one kg of inert binder/filler/diluent, to 100 kg; processing at each step the removed one kg of compound into 10,000 doses, or multiples thereof; continuing the portion-removal/reconstitutions, through the 100th portion-removal/reconstitution, with the dose being produced in the 100th step containing 0.005 (five one-thousandths) mg per 100 (hundred) mg tablet/dose; adding 101 (one hundred and one) kg, immediately following the 100th portion-removal, of inert mixture; mixing the resultant 200 (two hundred) kg mass to homogeneity, wherein said 200 kg batch is processed into doses of 100 mg that each contains 0.0025 (twenty-five ten-thousandths) mg of buprenorphine per 100 mg dose; removing 10 (ten) kg of said 200 kg of mixture to produce a number of doses equal to ten times the number of each previous week thereby providing ten weeks of a 0.0025 mg/100 mg dose, and; utilizing whatever portion of the remaining 190 kg of mixture is required for the final ten weeks of other regimens, this completing the manufacture of 114 weeks of doses containing active ingredient for a 118-week taper regimen. |
| Claim: | 6. A method of manufacture of claim 4 of medication for a taper regimen of doses of buprenorphine, with 99% of the reduction steps being in a linear fashion, with a duration of 218 weeks, wherein the manufactured product incorporates the following dosing requirements of starting at 0.5 (one-half) mg of buprenorphine, reducing manufactured doses in increments of 0.0025 (five one-thousandths) mg of buprenorphine, comprising: combining, through thorough mixing, 1.015 (one and fifteen-thousandths) kilograms (kg) of buprenorphine and 201.985 (two hundred point nine eight five) kg of inert filler/binder/diluent, the total mass being 203.000 kg of totally homogenous compound mixture; removing 4 (four) kg of this mixture, with each one kg of these removed 4 kg thereby containing 0.005 kg of buprenorphine per kg of mixture; manufacturing from these removed 4 kg, 100 mg tablets, each containing 0.5 mg buprenorphine/100 (milligram) mg dose or tablet, suitable for the first four weeks of the 218 week regimen; adding one kilogram of inert mixture to the 199 kg of compound mixture (said 199 kg consisting of active and inert ingredients as per immediately above) to make 200 kg of compound containing 0.995 (nine hundred and ninety-five thousandths) kg buprenorphine; removing 1 kg from the 200 kg reconstituted mass and processing into 100 mg tablets each containing 0.4975 mg buprenorphine, suitable for week 5 of the 218-week regimen; repeating the same procedure and replacing the removed 1 (one) kg with 1 (one) kg of inert filler/binder/diluent to produce through manufacturing processes a 100 mg dose containing 0.4950 mg of buprenorphine, suitable for the start of the second week of reduced dosages, which is the beginning of the 6 th week of the 218-week protocol; repeating this protocol 197 additional times, of removing one kg of active/inert compound and replacing with one kg of inert ingredients, and making 100 mg tablets, with each step producing a tablet containing 0.0025 less of buprenorphine than the previous step, until; producing in the final portion-removal/reconstitution process, 0.0025 mg per 100 mg tablet, each being one-quarter of the four times per day 0.01 mg daily dose, thereby having completed manufacture of 200 successive doses, each reducing by the amount of 0.0025 mg of buprenorphine. |
| Claim: | 7. A method of manufacture of claim 4 , of a taper regimen medication comprising the opioid buprenorphine in a uniformly saturated matrix of precisely cuttable film, suitable for sublingual or buccal use, of precisely known concentration; taking said film and cutting into smaller pieces, each now containing a precisely known amount of buprenorphine, including taking a sheet 10 cm×10 cm, containing 1.0 mg of buprenorphine total, or a sheet of film of any size with a known concentration of buprenorphine; cutting, the 10 cm×10 cm sheet into one hundred pieces of each 1 cm 2 , each square containing 0.01 mg of buprenorphine; combining these cut pieces so as to obtain any desired dose that is a multiple of 0.01 mg; initial sheets of different concentrations containing 0.5000, 0.4500, 0.4000, 0.3500, 0.3000, 0.2500, 0.2000, 0.1500, 0.1000, 0.0500 mg of buprenorphine are cut for dose ranges respectively of 0.4525-0.5000, 0.4025-0.4500, 0.3525-0.4000, 0.3025-0.3500, 0.2525-0.3000, 0.2025-0.2500, 0.1525-0.2000, 0.1025-0.1500, 0.0525-0.1000, 0.0025-0.0500 mg buprenorphine and combining said cut pieces for buccal or sublingual administration to produce any desired dose that is a multiple of 0.01 mg buprenorphine. |
| Patent References Cited: | 2010/0048535 February 2010 Slater 2011/0288113 November 2011 Peroutka |
| Other References: | Weinstein, Drug and Alcohol Dependence 189 (2018) 166-171 (Year: 2018). cited by examiner Horowitz et al. (Lancet Psychiatry 2019, 6: 538-46, Published online, Mar. 5, 2019) (Year: 2019). cited by examiner |
| Primary Examiner: | Ramachandran, Umamaheswari |
| رقم الانضمام: | edspgr.11253512 |
| قاعدة البيانات: | USPTO Patent Grants |
كن أول من يترك تعليقا!