Biopharmaceuticals – Su Il Yum, Wendy Chao, Huey-Ching Su, Roger Fu, Michael Zamloot, Durect Corp
Abstract for “Oral pharamaceutical dosage forms”
These forms are suitable for administering pharmacologically active substances and are abuse-resistant.
Background for “Oral pharamaceutical dosage forms”
There are many challenges in the delivery of drugs, especially oral delivery. The challenge lies in the creation of an oral controlled-release dosage that delivers a steady dose of drug for the eight hours it passes through the stomach. You can achieve sustained release by coating the tablet or making sure it dissolves slowly and releases the drug as it does. However, tablets once swallowed are subject to significant mechanical and chemical stress as they pass through the stomach, duodenum and jejunum, large intestine, colon and colon. This makes it difficult to maintain controlled drug release. Peristalsis, acids, enzymes and other chemicals can cause the tablet’s interior to be exposed and increase the surface area. This can increase the drug’s delivery rate or adversely affect controlled release properties.
“Another challenge is to create a dosage form that includes an oral dosage form. This will reduce the risk of drug abuse. Commonly, stimulants, CNS-depressants, as well as opioids are abused. A 1999 study by NIDA (National Institute on Drug Abuse) found that approximately 2 percent of people aged 12 and older were using prescription drugs “non-medically”. These included 2.6 million people who misused pain relief, 1.3 million misunderstood tranquilizers and sedatives, and 0.9 millions who misused stimulants.
“While many prescription drugs can be abused, the most common classes of abused drugs are: (1) Opioids?often prescribed to treat pain, (2) CNS Depressants?used to treat anxiety and sleep disorders, and (3) Stimulants?prescribed to treat narcolepsy and attention deficit/hyperactivity disorder.”
“Opioids can not only relieve pain but can also cause euphoria. If taken in large amounts, severe respiratory depression can occur which can lead to death.
CNS depressants slow down normal brain functions by increasing GABA activity. This causes a calming or drowsy effect. Some CNS depressants may be used as general anesthetics in higher doses. In extreme cases, they can cause respiratory failure or death. CNS depressants can be abused. Often, they are combined with other drugs or substances such as alcohol and cocaine. These drug abuses are responsible for many deaths each year. Based on the chemistry and pharmacology of CNS depressants, there are two types: (1) Barbiturates such as mephobarbital (e.g. Mebaral?) Pentobarbital sodium (e.g. Nembutal? These medications are used to treat anxiety, tension, sleep disorders, and other conditions. (2) Benzodiazepines such as diazepam (e.g. Valium?) chlordiazepoxide HCl (e.g. Librium? ), and alprazolam, (e.g. Xanax? ), which can be used to treat anxiety, panic attacks, acute stress reactions and panic attacks. Triazolam, a benzodiazepine that has a stronger sedating effect (e.g. Halcion?) Estazolam (e.g. ProSom?) For short-term treatment of sleeping disorders, ProSom can be used.
“Stimulants” are a group of drugs that increase brain activity. They cause an increase in alertness and attention that is accompanied with increases in blood pressure, heart beat, and respiration. Many stimulants are prescribed to treat narcolepsy and attention-deficit hyperactivity disorders (ADHD) as well as depression. Asthma patients and short-term obesity treatment may be possible with the help of stimulants. Dextroamphetamine (Dexedrine) are stimulants. Dextroamphetamine (Dexedrine) and methylphenidate, (Ritalin?) These chemicals have chemical structures similar to the monoamines (key brain neurotransmitters) norepinephrine, dopamine and methylphenidate (Ritalin). These chemicals are increased in the brain and body by stimulants. This causes an increase in blood pressure and heart beat, constricts blood vessels and increases blood glucose and opens up the respiratory system’s pathways. Additionally, these drugs can cause euphoria and an increase in dopamine.
High doses of stimulants can cause irregular heartbeats, high body temperatures, lethal seizures, and/or cardiovascular failure. Some people may feel hostility or paranoia if they take high doses of stimulants for a long time.
Mixing stimulants with antidepressants, over-the-counter cold medications containing decongestants or other drugs can lead to a dangerous and common cocktail. Combining stimulants with antidepressants can increase the effects of stimulants. In extreme cases, stimulants and decongestants can cause dangerously high blood pressure or irregular heart rhythms.
“Solid dosage forms are especially vulnerable to abuse. Tablets for oral drug delivery, such as tablets, can be ground into powder. To inhale the drug, drug addicts and abusers will grind the tablet. To make an injectable drug solution, addicts will also grind the tablet into alcohol or water. This method allows for a rapid increase in drug intake, resulting in a high level of euphoria. These techniques have been used for years to abuse all kinds of drugs.
These are abuse-resistant oral pharmaceutical dosage forms, which include a pharmacologically activated agent and a controlled delivery carrier system, are available. The present invention provides an oral pharmaceutical dosage form that contains a pharmacologically active ingredient and a controlled-release carrier system. In this case, the controlled release carrier includes a High Viscosity liquid carrier material (?HVLCM). A solvent, a hydrophilic, rheology modifier, and network former are all examples of the components. The present invention also aims to provide dosage forms that enhance in vivo absorption from the dosage form when it is combined with food or where the in vivo release from the controlled-release carrier system is substantially without any food effect. The invention also provides the above-described dosage forms in which the controlled release carrier system has a reduced risk of misuse and abuse. For example, the active ingredient is extracted from the dosage forms at a low level and/or there is no significant effect on the absorption of the active substance by subjects who consume the dosage form with alcohol. The controlled release carrier system may also be used to provide the following related objects: a unique combination of solvents, viscosity enhancers and other pharmaceutical excipients can be added to each of these items. The controlled release carrier system offers abuse-resistant properties to its dosage form. Accordingly, it is a related object to the invention to provide the described dosage form. The controlled release carrier system may also include one or more of these additional components: a viscosity-enhancing agent; and a stabilizing agents. The HVLCM may include sucrose acetate butyrate (?SAIB) in particular embodiments. The network former can include cellulose acetate phthalate (?SAIB?). ), cellulose butyrate, ethylcellulose, hydroxypropylmethylcellulose, or cellulose triacetate. The rheology modifier may include isopropyl myristate, (?IPM?) ), caprylic/capric triglyceride, ethyl oleate, triethyl citrate, dimethyl phthalate or benzyl benzoate; the hydrophilic agent can comprise hydroxyethylcellulose (?HEC? ), hydroxypropylcellulose, caboxymethylcellulose, polyethylene glycol or polyvinylpyrrolidone; and the solvent can comprise triacetin, N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethylsulfoxide, ethyl lactate, propylene carbonate or glycofurol. The viscosity enhancing agents can also include silicon dioxide. Additionally, the stabilizer can contain butylhydroxyltoluene (??BHT?). Preferably, the active agent may be an opioid, CNS depressant, or CNS stimulant with a high potential for abuse or diversion. The active agent is preferred to be an opioid, amphetamine or methylphenidate. Each case can either be a salt, or a free base.
“It is another object to the invention to provide an oral pharmaceutical dosage format that includes a drugcologically active agent as well as a controlled release carrier system. A High Viscosity Liquid Carrrier Material (?HVLCM?) is part of the controlled release carrier system. The controlled release carrier system includes a High Viscosity Liquid Carrier Material (?HVLCM) and a hydrophilic collvent. The present invention also aims to provide dosage forms that enhance in vivo absorption from the dosage forms when they are administered with food or where the in vivo release from the controlled-release carrier system is substantially without any food effect. The invention also provides the above-described dosage forms in which the controlled release carrier system has a reduced risk of misuse and abuse. For example, the active ingredient is extracted from the dosage forms at a low level and/or there is no significant effect on the absorption of the active substance by subjects who consume the dosage form with alcohol. The controlled release carrier system may also be used to provide the following related objects: a unique combination of solvents, viscosity enhancers and other pharmaceutical excipients can be added to each of these items. The controlled release carrier system offers abuse-resistant properties to dosage forms. In certain preferred embodiments, the network former can comprise CAB, cellulose acetate phthalate, ethyl cellulose, hydroxypropylmethyl cellulose or cellulose triacetate; the first viscosity enhancing agent can comprise HEC, hydroxypropylcellulose, carboxymethylcellulose, polyethylene glycol or polyvinylpyrrolidone; the hydrophilic solvent can comprise triacetin, N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethylsulfoxide, ethyl lactate, propylene carbonate or glycofurol; and the hydrophobic solvent can comprise IPM. The active agent may also include an opioid, CNS depressant, or CNS stimulant with a high potential for abuse or diversion. The active agent should consist of an opioid, an amphetamine or a methylphenidate. Each case can be either a salt, or a free base.
“It is also an object of the invention that a method for the preparation oral pharmaceutical dosage forms includes a pharmacologically activated agent and a controlled-release carrier system. The controlled-release carrier system includes a High Viscosity Liquid Carrrier Material (?HVLCM)? A solvent, a solvent, a rheology modifier, and a hydrophilic agents are all required. The manufacturing or compounding steps include: heating the HVLCM, mixing the solvent and the preheated HPLM to make a uniform solution; dispersing network formers in the solution to dissolve them in the solution; adding the pharmacologically effective agent to the formulation; adding and mixing the viscosity enhancer; and optionally adding and mixing the remaining rheology modifiable. The process may also include filling capsules with the prepared formulation and packaging them into multidose plastic bottles or unit dose blisters. The invention also provides a method for making an oral pharmaceutical dosage form. This controlled release carrier system includes a HVLCM and a network former. The manufacturing or compounding steps include: heating the HVLCM, mixing the solvent and the preheated HPLM to form a uniform solution; optionally, adding and stirring the stabilizing agent or, if necessary, the balance of a rheology modifier with the solution obtained earlier; optionally adding and mixing a viscosity-enhancing agent with formulation obtained in previous step; dissolving the network founder in the solution by adding and mixing it with the formulation obtained from the previous step; and finally adding and pharmacologically activate agent to the formulation; and mixing with the hydrophilic agent; and then adding and mix the hydrophilic acid agent; and mixing with the preparation; and mixing the hydrophilic agents with the mixture with the previously. The process may also include filling capsules with the formula obtained during the process, and optionally packaging them into multidose plastic bottles or unit dose blisters. The present invention also aims to provide an oral dosage form for pharmaceuticals that can be made using the above manufacturing and compounding processes.
The invention also aims to provide a method for making an oral pharmaceutical dosage form. This includes a pharmacologically activated agent and a controlled-release carrier system. The controlled release carrier includes a HVLCM and a network former. It can also include a HVLCM, first viscosity enhancer, a hydrophilic solvent, and a hydrophobic solvent. The manufacturing or compounding steps include: heating the HVLCM, mixing the solvent and the preheated HPLM to make a uniform solution of HVLCM in solvent, dispersing the network founder in the solution to dissolve it in the solution, mixing 5 to 30% or more of the stabilizing agent with the formulation, adding and mixing the pharmaceutically active agent, the viscosity-enhancing agent, and optionally adding and mixing the remaining rheology moderator. The process may also include filling capsules with the prepared formulation and packaging them into multidose plastic bottles or unit dose blisters. The invention also provides a method for the preparation an oral pharmaceutical dosage form. This controlled release carrier includes a pharmacologically activated agent and a controlled delivery system. The manufacturing or compounding steps include: heating the HVLCM, mixing the solvent and the preheated HPLM to form a uniform solution of HVLCM in solvent; optionally mixing a solution containing a stabilising agent or from 5 to 30% rheology moderator with the solution obtained earlier; optionally adding and mixing a viscosity-enhancing agent with formulation obtained in previous step; dissolving the network founder in the solution by adding and mixing it with the formulation obtained previously; and finally, and mixing the pharmaceutically active agent with that was obtained in step and then adding and mixing with the preparation; and mixing the hydrophilic acid. The process may also include filling capsules with the formula obtained during the process, and optionally packaging them into multidose plastic bottles or unit dose blisters. The present invention also aims to provide an oral dosage form for pharmaceuticals that can be made using the above manufacturing and compounding processes.
“A further object of the invention is to provide an abuse-resistant oral pharmaceutical dosage format that contains a pharmacologically active drug and a controlled release carrier. The controlled release carrier system allows for controlled in-vivo release of an agent. It is distinguished by the fact that the individual steady-state Cmin/Cmax variance during an interdose interval equals or less than the Therapeutic Index. The present invention also aims to provide an abuse-resistant oral pharmaceutical dosage format that contains a pharmacologically active drug and a controlled-release carrier system. This dosage form can be used in a BID-dosing regime. The invention also provides the above-described dosage form whose in vivo pharmacological performance can be described by having an individual Cmin/Cmax variance of about 2 to 3, when administered at the therapeutically effective dose (or AUC). The invention also provides the above-described dosage formats where the controlled-release carrier system further reduces the risk of misuse and abuse. For example, the in vitro solvent extractability of the active ingredient from the dosage forms and/or the absence of any significant effect upon absorption of active agent from dosage form when the dosage form is combined with alcohol is another related object. The controlled release carrier system may also be distinguished by unique pharmaceutical excipients such as solvents, carrier materials and viscosity-enhancing agents. Preferably, the active agent may be an opioid, CNS depressant, or CNS stimulant with a high potential for abuse or diversion. The active agent is preferred to be an opioid, amphetamine or methylphenidate. Each case can either be a salt, or a free base.
The present invention also aims to provide an abuse-resistant oral pharmaceutical dosage format that contains a pharmacologically active ingredient and a controlled delivery carrier system. The controlled release carrier system allows for controlled in-vivo release. It is distinguished by the fact that the individual steady-state Cmin/Cmax variance in an interdose interval is less or equal to the Therapeutic Index. However, the in vivo absorption from the dosage forms is increased upon administration of the dosage forms with food. However, the dosage forms are still safe when taken unprescribed, such as without food. The present invention also aims to provide an abuse-resistant oral pharmaceutical dosage format that contains a pharmacologically active ingredient and a controlled-release carrier system. Further, the dosage form can be used in a BID-dosing regime and the in vivo absorption is enhanced by the addition of food to the dosage forms. The invention also provides the above-described dosage form whose in vivo pharmacological performance can be described by having an individual Cmin/Cmax variance of about 2 to 3. The invention also provides the above-described dosage formats where the controlled-release carrier system further reduces the risk of misuse and abuse. For example, the in vivo pharmacological performance is defined by an individual Cmin/Cmax variance at steady state that is less than or equal to about 2 to 3. The controlled release carrier system may also be distinguished by unique pharmaceutical excipients such as solvents, carrier materials and network fortifiers. Preferably, the active agent may be an opioid, CNS depressant, or CNS stimulant with a high potential for abuse or diversion. The active agent is preferred to be an opioid, amphetamine or methylphenidate. Each case can either be a salt, or a free base.
“A further object of the invention is to provide an abuse-resistant oral medication dosage form that contains an opioid analgesic and a controlled delivery carrier system. The controlled release carrier provides controlled in-vivo release of an agent. This is accomplished by ensuring that the individual steady state Cmin/Cmax variance in an interdose interval is less or equal to the Therapeutic Index. Furthermore, the pharmacokinetic in-vivo release performance for the opioid analgesic agents from the controlled release carriers system is at least 4 hours after the subject has inhaled the drug. The present invention also aims to provide an abuse-resistant oral pharmaceutical dosage format that contains an opioid analgesic and a controlled-release carrier system. Further, the Tmax of the controlled-release carrier system’s pharmacokinetic in-vivo release performance for the opioid analgesic is at least 4 hours after the subject has inhaled it. The invention also provides the above-described dosage forms that enhance the in vivo absorption and release of opioid analgesic agents from the dosage forms. The invention also provides the above-described dosage form whose in vivo pharmacological performance can be described by having an individual Cmin/Cmax variance of about 2 to 3. The invention also provides the above-described dosage formats where the controlled-release carrier system provides a reduced risk of misuse and abuse. For example, the in vivo pharmacological performance of the dosage forms is characterised by a low in vitro solvent extraction value for the opioid analgesic agents from the dosage forms and/or the absence of any significant effect upon absorption of opioid analgesic agents from the dosage forms when the dosage form is combined with alcohol. The controlled release carrier system may also be distinguished by unique pharmaceutical excipients such as solvents, carrier materials and network forerunners.
“An abuse-resistant oral pharmaceutical dosage form containing a pharmacologically active drug and a controlled release carrier is an additional object of the present invention. The controlled release carrier system allows for controlled in-vivo release of an agent. It is distinguished by the fact that the individual steady-state Cmin/Cmax variance during an interdose interval falls below or equal to the Therapeutic Index. Additionally, the carrier system contains a High Viscosity liquid carrier material (?HVLCM). A network former and at most one viscosity-enhancing agent. The present invention also aims to provide an abuse-resistant oral pharmaceutical dosage format that contains a pharmacologically active ingredient and a controlled-release carrier system. This dosage form can be used in a BID-dosing regime and further, the controlled-release carrier system may include a High Viscosity liquid carrier material (?HVLCM). A network former and at most one viscosity-enhancing agent. The invention also provides the above-described dosage forms in which the in vivo absorption is increased upon administration of dosage form with food or vice versa. The invention also provides the above-described dosage form whose in vivo pharmacological performance can be described by having an individual Cmin/Cmax variance of about 2 to 3. The invention also provides the above-described dosage formats where the controlled-release carrier system further reduces the risk of misuse and abuse. For example, the in vivo solvent extractability value for the active ingredient from the dosage forms is low and/or the lack of significant effects on absorption of active agent from dosage form when the dosage form is combined with alcohol. The controlled release carrier system may also be distinguished by unique pharmaceutical excipients that include certain combinations of solvents and viscosity-enhancing agents. Preferably, the active agent may be an opioid, CNS depressant, or CNS stimulant with a high potential for abuse or diversion. The active agent is preferred to be an opioid, amphetamine or methylphenidate. Each case can either be a salt, or a free base.
“It is also the object of this invention to provide an abuse resistant oral pharmaceutical dosage form that contains a pharmacologically active drug and a controlled-release carrier system. The controlled release carrier system allows for controlled in-vivo release of an agent. This is characterized by a steady state Cmin/Cmax variation that is less or equal to the Therapeutic Index. More specifically, this is a steady state Cmin/Cmax variation that is less or equal to 2 to 3. The present invention also aims to provide an abuse-resistant oral pharmaceutical dosage format that contains a pharmacologically active ingredient and a controlled-release carrier system. In particular, the individual Cmin/Cmax variance at steady state is less than or equal to about 2 to 3. The invention also provides the above-described dosage forms in which the in vivo absorption is increased upon administration of the dosage formula with food or where the in vivo release is substantially free of food effects. The invention also provides the above-described dosage forms in which the controlled release carrier system has a reduced risk of misuse and abuse. For example, the dosage forms are characterised by low in vitro solvent extraction values of the active agents and/or no significant effect on absorption by subjects of the dosage forms and alcohol. The controlled release carrier system may also be distinguished by unique pharmaceutical excipients that include certain combinations of solvents and viscosity-enhancing agents. Preferably, the active agent may be an opioid, CNS depressant, or CNS stimulant with a high potential for abuse or diversion. The active agent is preferred to be an opioid, amphetamine or methylphenidate. Each case can either be a salt, or a free base.
“The present invention also aims to provide an abuse-resistant oral pharmaceutical dosage format that contains a pharmacologically active ingredient and a controlled delivery carrier system. A High Viscosity Liquid Carrrier Material (?HVLCM?) is part of the controlled release carrier system. The controlled release carrier system includes a High Viscosity Liquid Carrier Material (?HVLCM?) and at least one viscosity-enhancing agent. The present invention also aims to provide dosage forms that enhance in vivo absorption from the dosage form when it is combined with food or where the in vivo release from the controlled-release carrier system is virtually free from any food effects. The invention also provides the above-described dosage forms in which the controlled release carrier system has a reduced risk of misuse and abuse. For example, the controlled release carrier system is low in vitro solvent extraction value and/or does not have any significant effect upon absorption of active agent from dosage form when the dosage form is combined with alcohol. The controlled release carrier system may also be distinguished by unique pharmaceutical excipients that include certain combinations of solvents and viscosity-enhancing agents. Preferably, the active agent may be an opioid, CNS depressant, or CNS stimulant with a high potential for abuse or diversion. The active agent is preferred to be an opioid, amphetamine or methylphenidate. Each case can either be a salt, or as a freebase.
“Another object of the invention is to provide an abuse resistant oral pharmaceutical dosage form that includes a pharmacologically active ingredient and a controlled-release carrier system. The carrier system is capable of providing at least 8 hours’ of substantially constant in vitro release when tested in an USP Type II dissolution apparatus with a stationary basket assembly. 20% or less of active agent can be extracted from the dosage form using EtOH (100 proof), as an extraction solvent at ambient temperature (RT) for one hour. The invention also provides an abuse-resistant oral pharmaceutical dosage format that includes a pharmacologically active ingredient and a controlled delivery carrier system. According to the invention, the carrier system provides at most 8 hours of substantially continuous in vitro release when tested in an USP Type II dissolution apparatus with a stationary basket assembly at 100 rpm and 0.1%N HCl dissolution medium containing surfactant. 30% or less of active agent can be extracted from the dosage form in an in vitro solvent extract test at ambient temperature (RT) for 1 hour
“It is another object of the invention that an oral pharmaceutical dosage form includes a drug agent and a controlled delivery carrier system. The controlled release carrier includes an HVLCM and a network foreman, a rheology modifier and a hydrophilic ingredient. The dosage form is also abuse-resistant. The invention also provides the described dosage form. However, the controlled release carrier system may include one or more of these additional components: a viscosity enhancer; solvent; and stabilizer agent. The HVLCM may include sucrose acetate butyrate (?SAM) in particular embodiments. The network former can include cellulose acetatebutyrate (?CAB?) The rheology modifier may include isopropyl myristate, (?IPM) The hydrophilic agent may contain hydroxyethylcellulose (?HEC?) The hydrophilic agent can contain hydroxyethyl cellulose (?HEC?). The active agent may contain an opioid as either a salt or a free base.
“It is an additional object of the invention that safer methods of treatment (including palliative) are provided to patients who require such treatment. These methods include administration of the abuse-resistant oral prescription dosage forms of this invention. The invention aims to provide a method for maintaining and establishing analgesia in a subject through repeated administration of an oral analgesic dose form. This dosage form is safe and can be used safely. In the instant method, the dosage form includes an analgesic and a controlled release carrier system. The controlled release carrier allows for controlled in-vivo release. This is characterized by a steady state Cmin/Cmax variation that is less or equal to the Therapeutic Index. The present invention also aims to provide a method of establishing and maintaining analgesia for a subject through repeated administration of an oral painkiller dosage form. This dosage form is safe and suitable for use in a BID dosing regimen. The invention also provides methods where the in vivo pharmaceutical performance of the dosage forms can be measured by having an individual Cmin/Cmax variance of about 2 to 3. The invention also provides methods wherein the in vivo pharmacological performance of dosage forms is reduced by having individual Cmin/Cmax variance at steady state that is less than or equal to about 2 to 3. A further object of this invention is to provide a method of maintaining and establishing analgesia in a subject through repeated administration of an abuse-resistant oral painkiller dosage form. This dosage form can be enhanced in that the bioavailability (e.g., in vivo absorption) of the analgesic agents is increased upon the co-administration with food. The methods include repeated administration of the dosage forms if the analgesic agent in question is an opioid. In a preferred embodiment, however, the opioid is in the dosage form in its base form.
“It is another object in the invention to provide a method of establishing and maintaining analgesia for a subject through repeated administration of an oral medication. The controlled release carrier includes an analgesic and analgesic agent. The controlled release carrier includes an HVLCM, an HVLCM, and at least one viscosity-enhancing agent. The dosage form is also safe and resistant to abuse, making it safer for patients. Another related object is to provide a method of establishing and maintaining analgesia for a subject through repeated administration of an oral painkiller dosage form. The dosage form also includes the described controlled release carrier system. This allows for controlled in-vivo release of analgesic agents. It is characterized by a steady state Cmin/Cmax variance that is less or equal to the Therapeutic Index. The present invention also aims to provide a method of establishing and maintaining analgesia for a subject through repeated administration of an oral painkiller dosage form. This dosage form can be used in a BID-dosing regimen. The invention also provides methods where the in vivo pharmaceutical performance of the dosage forms can be measured by having an individual Cmin/Cmax variance of about 2 to 3. The invention also provides methods wherein the in vivo pharmacological performance of dosage forms is reduced by having individual Cmin/Cmax variance at steady state that is less than or equal to about 2 to 3. A further object of this invention is to provide a method of maintaining and establishing analgesia in a subject through repeated administration of an abuse-resistant oral painkiller dosage form. This dosage form can be enhanced in that the bioavailability (i.e., in vivo absorption) of the analgesic agents is increased upon the co-administration with food. The methods include repeated administration of the dosage forms if the analgesic agent in question is an opioid. In a preferred embodiment, however, the opioid is in the dosage form in its base form.
The present invention has the advantage that abuse-resistant oral dosage forms can provide enhanced safety features and/or misuse-resistance qualities, in addition to improved in-vivo pharmacological performances. The invention also has the advantage that inventive dosage forms are easy to construct and can be used to offer a wider range of safer and more effective pharmacological solutions for the medical field.
“These and other aspects, advantages and objects of the invention will be readily apparent to the skilled person after reading the instant disclosure.
“POINTS ON THE INVENTION”
“1. “1. A controlled release pharmaceutical dosage form that contains a pharmacologically active drug and a controlled delivery carrier system. It includes:
“2. “2.
“3. “3.
“4. “4.
“5. “5.
“6. “6.
“7. “7.
“8. “8.
“9. “9.
“10. “10.
“11. “11.
“12. “12.
“13. “13.
“14. “14.
“15. “15.
“16. “16.
“17. “17.
“18. “18.
“19. “19.
“20. “20.
“21. “21.
“23. “23.
“24. The dosage form of point 23, wherein the capsule comprises gelatin, hydroxyethylcellulose or hydroxypropylmethylcellulose.”
“25. “25.
“26. “26.
“27. “27.
“28. “28.
“29. “29.
“30. A form of oral pharmaceutical dosage that can be obtained by following the process described in points 26-29.
“31. “31.
“32. “32.
“33. “33.
“34. “34.
“35. “35.
“36. “36.
“37. “37.
“38. “38.
“39. “39.
“40. “40.
“41. “41.
“42. “42.
“43. “43.
“44. “44.
“45. “45.
“46. “46.
“47. “47.
“48. Point 46 is the dosage form, in which individual Cmin/Cmax variations at steady state are less than or equals to 2 to 3.
“49. Point 46 is the dosage form that can be used in a BID-dosing program.
“50. Point 46 is the dosage form in which the active agent is an opioid.
“51. Point 46. The dosage form in which the active agent is given as a free base.
“52. “52.
“53. “53.
“54. “54.
“55. “55.
“56. “56.
“57. “57.
“58. “58.
“59. “59.
“60. “60.
“61. Method to increase the oral bioavailability and effectiveness of active agents to subjects receiving treatment with them. This method involves orally administering the dosage form described at point 46 to the subject with food.
“62. Method to increase the absorption of active agents from oral dosage forms. This method involves orally administering to the subject dosage form 46 along with food.
“63. “63.
“64. “64.
“65. “65.
“66. “66.
“67. “67.
“68. “68.
“69. “69.
“70. “70.
Summary for “Oral pharamaceutical dosage forms”
There are many challenges in the delivery of drugs, especially oral delivery. The challenge lies in the creation of an oral controlled-release dosage that delivers a steady dose of drug for the eight hours it passes through the stomach. You can achieve sustained release by coating the tablet or making sure it dissolves slowly and releases the drug as it does. However, tablets once swallowed are subject to significant mechanical and chemical stress as they pass through the stomach, duodenum and jejunum, large intestine, colon and colon. This makes it difficult to maintain controlled drug release. Peristalsis, acids, enzymes and other chemicals can cause the tablet’s interior to be exposed and increase the surface area. This can increase the drug’s delivery rate or adversely affect controlled release properties.
“Another challenge is to create a dosage form that includes an oral dosage form. This will reduce the risk of drug abuse. Commonly, stimulants, CNS-depressants, as well as opioids are abused. A 1999 study by NIDA (National Institute on Drug Abuse) found that approximately 2 percent of people aged 12 and older were using prescription drugs “non-medically”. These included 2.6 million people who misused pain relief, 1.3 million misunderstood tranquilizers and sedatives, and 0.9 millions who misused stimulants.
“While many prescription drugs can be abused, the most common classes of abused drugs are: (1) Opioids?often prescribed to treat pain, (2) CNS Depressants?used to treat anxiety and sleep disorders, and (3) Stimulants?prescribed to treat narcolepsy and attention deficit/hyperactivity disorder.”
“Opioids can not only relieve pain but can also cause euphoria. If taken in large amounts, severe respiratory depression can occur which can lead to death.
CNS depressants slow down normal brain functions by increasing GABA activity. This causes a calming or drowsy effect. Some CNS depressants may be used as general anesthetics in higher doses. In extreme cases, they can cause respiratory failure or death. CNS depressants can be abused. Often, they are combined with other drugs or substances such as alcohol and cocaine. These drug abuses are responsible for many deaths each year. Based on the chemistry and pharmacology of CNS depressants, there are two types: (1) Barbiturates such as mephobarbital (e.g. Mebaral?) Pentobarbital sodium (e.g. Nembutal? These medications are used to treat anxiety, tension, sleep disorders, and other conditions. (2) Benzodiazepines such as diazepam (e.g. Valium?) chlordiazepoxide HCl (e.g. Librium? ), and alprazolam, (e.g. Xanax? ), which can be used to treat anxiety, panic attacks, acute stress reactions and panic attacks. Triazolam, a benzodiazepine that has a stronger sedating effect (e.g. Halcion?) Estazolam (e.g. ProSom?) For short-term treatment of sleeping disorders, ProSom can be used.
“Stimulants” are a group of drugs that increase brain activity. They cause an increase in alertness and attention that is accompanied with increases in blood pressure, heart beat, and respiration. Many stimulants are prescribed to treat narcolepsy and attention-deficit hyperactivity disorders (ADHD) as well as depression. Asthma patients and short-term obesity treatment may be possible with the help of stimulants. Dextroamphetamine (Dexedrine) are stimulants. Dextroamphetamine (Dexedrine) and methylphenidate, (Ritalin?) These chemicals have chemical structures similar to the monoamines (key brain neurotransmitters) norepinephrine, dopamine and methylphenidate (Ritalin). These chemicals are increased in the brain and body by stimulants. This causes an increase in blood pressure and heart beat, constricts blood vessels and increases blood glucose and opens up the respiratory system’s pathways. Additionally, these drugs can cause euphoria and an increase in dopamine.
High doses of stimulants can cause irregular heartbeats, high body temperatures, lethal seizures, and/or cardiovascular failure. Some people may feel hostility or paranoia if they take high doses of stimulants for a long time.
Mixing stimulants with antidepressants, over-the-counter cold medications containing decongestants or other drugs can lead to a dangerous and common cocktail. Combining stimulants with antidepressants can increase the effects of stimulants. In extreme cases, stimulants and decongestants can cause dangerously high blood pressure or irregular heart rhythms.
“Solid dosage forms are especially vulnerable to abuse. Tablets for oral drug delivery, such as tablets, can be ground into powder. To inhale the drug, drug addicts and abusers will grind the tablet. To make an injectable drug solution, addicts will also grind the tablet into alcohol or water. This method allows for a rapid increase in drug intake, resulting in a high level of euphoria. These techniques have been used for years to abuse all kinds of drugs.
These are abuse-resistant oral pharmaceutical dosage forms, which include a pharmacologically activated agent and a controlled delivery carrier system, are available. The present invention provides an oral pharmaceutical dosage form that contains a pharmacologically active ingredient and a controlled-release carrier system. In this case, the controlled release carrier includes a High Viscosity liquid carrier material (?HVLCM). A solvent, a hydrophilic, rheology modifier, and network former are all examples of the components. The present invention also aims to provide dosage forms that enhance in vivo absorption from the dosage form when it is combined with food or where the in vivo release from the controlled-release carrier system is substantially without any food effect. The invention also provides the above-described dosage forms in which the controlled release carrier system has a reduced risk of misuse and abuse. For example, the active ingredient is extracted from the dosage forms at a low level and/or there is no significant effect on the absorption of the active substance by subjects who consume the dosage form with alcohol. The controlled release carrier system may also be used to provide the following related objects: a unique combination of solvents, viscosity enhancers and other pharmaceutical excipients can be added to each of these items. The controlled release carrier system offers abuse-resistant properties to its dosage form. Accordingly, it is a related object to the invention to provide the described dosage form. The controlled release carrier system may also include one or more of these additional components: a viscosity-enhancing agent; and a stabilizing agents. The HVLCM may include sucrose acetate butyrate (?SAIB) in particular embodiments. The network former can include cellulose acetate phthalate (?SAIB?). ), cellulose butyrate, ethylcellulose, hydroxypropylmethylcellulose, or cellulose triacetate. The rheology modifier may include isopropyl myristate, (?IPM?) ), caprylic/capric triglyceride, ethyl oleate, triethyl citrate, dimethyl phthalate or benzyl benzoate; the hydrophilic agent can comprise hydroxyethylcellulose (?HEC? ), hydroxypropylcellulose, caboxymethylcellulose, polyethylene glycol or polyvinylpyrrolidone; and the solvent can comprise triacetin, N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethylsulfoxide, ethyl lactate, propylene carbonate or glycofurol. The viscosity enhancing agents can also include silicon dioxide. Additionally, the stabilizer can contain butylhydroxyltoluene (??BHT?). Preferably, the active agent may be an opioid, CNS depressant, or CNS stimulant with a high potential for abuse or diversion. The active agent is preferred to be an opioid, amphetamine or methylphenidate. Each case can either be a salt, or a free base.
“It is another object to the invention to provide an oral pharmaceutical dosage format that includes a drugcologically active agent as well as a controlled release carrier system. A High Viscosity Liquid Carrrier Material (?HVLCM?) is part of the controlled release carrier system. The controlled release carrier system includes a High Viscosity Liquid Carrier Material (?HVLCM) and a hydrophilic collvent. The present invention also aims to provide dosage forms that enhance in vivo absorption from the dosage forms when they are administered with food or where the in vivo release from the controlled-release carrier system is substantially without any food effect. The invention also provides the above-described dosage forms in which the controlled release carrier system has a reduced risk of misuse and abuse. For example, the active ingredient is extracted from the dosage forms at a low level and/or there is no significant effect on the absorption of the active substance by subjects who consume the dosage form with alcohol. The controlled release carrier system may also be used to provide the following related objects: a unique combination of solvents, viscosity enhancers and other pharmaceutical excipients can be added to each of these items. The controlled release carrier system offers abuse-resistant properties to dosage forms. In certain preferred embodiments, the network former can comprise CAB, cellulose acetate phthalate, ethyl cellulose, hydroxypropylmethyl cellulose or cellulose triacetate; the first viscosity enhancing agent can comprise HEC, hydroxypropylcellulose, carboxymethylcellulose, polyethylene glycol or polyvinylpyrrolidone; the hydrophilic solvent can comprise triacetin, N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethylsulfoxide, ethyl lactate, propylene carbonate or glycofurol; and the hydrophobic solvent can comprise IPM. The active agent may also include an opioid, CNS depressant, or CNS stimulant with a high potential for abuse or diversion. The active agent should consist of an opioid, an amphetamine or a methylphenidate. Each case can be either a salt, or a free base.
“It is also an object of the invention that a method for the preparation oral pharmaceutical dosage forms includes a pharmacologically activated agent and a controlled-release carrier system. The controlled-release carrier system includes a High Viscosity Liquid Carrrier Material (?HVLCM)? A solvent, a solvent, a rheology modifier, and a hydrophilic agents are all required. The manufacturing or compounding steps include: heating the HVLCM, mixing the solvent and the preheated HPLM to make a uniform solution; dispersing network formers in the solution to dissolve them in the solution; adding the pharmacologically effective agent to the formulation; adding and mixing the viscosity enhancer; and optionally adding and mixing the remaining rheology modifiable. The process may also include filling capsules with the prepared formulation and packaging them into multidose plastic bottles or unit dose blisters. The invention also provides a method for making an oral pharmaceutical dosage form. This controlled release carrier system includes a HVLCM and a network former. The manufacturing or compounding steps include: heating the HVLCM, mixing the solvent and the preheated HPLM to form a uniform solution; optionally, adding and stirring the stabilizing agent or, if necessary, the balance of a rheology modifier with the solution obtained earlier; optionally adding and mixing a viscosity-enhancing agent with formulation obtained in previous step; dissolving the network founder in the solution by adding and mixing it with the formulation obtained from the previous step; and finally adding and pharmacologically activate agent to the formulation; and mixing with the hydrophilic agent; and then adding and mix the hydrophilic acid agent; and mixing with the preparation; and mixing the hydrophilic agents with the mixture with the previously. The process may also include filling capsules with the formula obtained during the process, and optionally packaging them into multidose plastic bottles or unit dose blisters. The present invention also aims to provide an oral dosage form for pharmaceuticals that can be made using the above manufacturing and compounding processes.
The invention also aims to provide a method for making an oral pharmaceutical dosage form. This includes a pharmacologically activated agent and a controlled-release carrier system. The controlled release carrier includes a HVLCM and a network former. It can also include a HVLCM, first viscosity enhancer, a hydrophilic solvent, and a hydrophobic solvent. The manufacturing or compounding steps include: heating the HVLCM, mixing the solvent and the preheated HPLM to make a uniform solution of HVLCM in solvent, dispersing the network founder in the solution to dissolve it in the solution, mixing 5 to 30% or more of the stabilizing agent with the formulation, adding and mixing the pharmaceutically active agent, the viscosity-enhancing agent, and optionally adding and mixing the remaining rheology moderator. The process may also include filling capsules with the prepared formulation and packaging them into multidose plastic bottles or unit dose blisters. The invention also provides a method for the preparation an oral pharmaceutical dosage form. This controlled release carrier includes a pharmacologically activated agent and a controlled delivery system. The manufacturing or compounding steps include: heating the HVLCM, mixing the solvent and the preheated HPLM to form a uniform solution of HVLCM in solvent; optionally mixing a solution containing a stabilising agent or from 5 to 30% rheology moderator with the solution obtained earlier; optionally adding and mixing a viscosity-enhancing agent with formulation obtained in previous step; dissolving the network founder in the solution by adding and mixing it with the formulation obtained previously; and finally, and mixing the pharmaceutically active agent with that was obtained in step and then adding and mixing with the preparation; and mixing the hydrophilic acid. The process may also include filling capsules with the formula obtained during the process, and optionally packaging them into multidose plastic bottles or unit dose blisters. The present invention also aims to provide an oral dosage form for pharmaceuticals that can be made using the above manufacturing and compounding processes.
“A further object of the invention is to provide an abuse-resistant oral pharmaceutical dosage format that contains a pharmacologically active drug and a controlled release carrier. The controlled release carrier system allows for controlled in-vivo release of an agent. It is distinguished by the fact that the individual steady-state Cmin/Cmax variance during an interdose interval equals or less than the Therapeutic Index. The present invention also aims to provide an abuse-resistant oral pharmaceutical dosage format that contains a pharmacologically active drug and a controlled-release carrier system. This dosage form can be used in a BID-dosing regime. The invention also provides the above-described dosage form whose in vivo pharmacological performance can be described by having an individual Cmin/Cmax variance of about 2 to 3, when administered at the therapeutically effective dose (or AUC). The invention also provides the above-described dosage formats where the controlled-release carrier system further reduces the risk of misuse and abuse. For example, the in vitro solvent extractability of the active ingredient from the dosage forms and/or the absence of any significant effect upon absorption of active agent from dosage form when the dosage form is combined with alcohol is another related object. The controlled release carrier system may also be distinguished by unique pharmaceutical excipients such as solvents, carrier materials and viscosity-enhancing agents. Preferably, the active agent may be an opioid, CNS depressant, or CNS stimulant with a high potential for abuse or diversion. The active agent is preferred to be an opioid, amphetamine or methylphenidate. Each case can either be a salt, or a free base.
The present invention also aims to provide an abuse-resistant oral pharmaceutical dosage format that contains a pharmacologically active ingredient and a controlled delivery carrier system. The controlled release carrier system allows for controlled in-vivo release. It is distinguished by the fact that the individual steady-state Cmin/Cmax variance in an interdose interval is less or equal to the Therapeutic Index. However, the in vivo absorption from the dosage forms is increased upon administration of the dosage forms with food. However, the dosage forms are still safe when taken unprescribed, such as without food. The present invention also aims to provide an abuse-resistant oral pharmaceutical dosage format that contains a pharmacologically active ingredient and a controlled-release carrier system. Further, the dosage form can be used in a BID-dosing regime and the in vivo absorption is enhanced by the addition of food to the dosage forms. The invention also provides the above-described dosage form whose in vivo pharmacological performance can be described by having an individual Cmin/Cmax variance of about 2 to 3. The invention also provides the above-described dosage formats where the controlled-release carrier system further reduces the risk of misuse and abuse. For example, the in vivo pharmacological performance is defined by an individual Cmin/Cmax variance at steady state that is less than or equal to about 2 to 3. The controlled release carrier system may also be distinguished by unique pharmaceutical excipients such as solvents, carrier materials and network fortifiers. Preferably, the active agent may be an opioid, CNS depressant, or CNS stimulant with a high potential for abuse or diversion. The active agent is preferred to be an opioid, amphetamine or methylphenidate. Each case can either be a salt, or a free base.
“A further object of the invention is to provide an abuse-resistant oral medication dosage form that contains an opioid analgesic and a controlled delivery carrier system. The controlled release carrier provides controlled in-vivo release of an agent. This is accomplished by ensuring that the individual steady state Cmin/Cmax variance in an interdose interval is less or equal to the Therapeutic Index. Furthermore, the pharmacokinetic in-vivo release performance for the opioid analgesic agents from the controlled release carriers system is at least 4 hours after the subject has inhaled the drug. The present invention also aims to provide an abuse-resistant oral pharmaceutical dosage format that contains an opioid analgesic and a controlled-release carrier system. Further, the Tmax of the controlled-release carrier system’s pharmacokinetic in-vivo release performance for the opioid analgesic is at least 4 hours after the subject has inhaled it. The invention also provides the above-described dosage forms that enhance the in vivo absorption and release of opioid analgesic agents from the dosage forms. The invention also provides the above-described dosage form whose in vivo pharmacological performance can be described by having an individual Cmin/Cmax variance of about 2 to 3. The invention also provides the above-described dosage formats where the controlled-release carrier system provides a reduced risk of misuse and abuse. For example, the in vivo pharmacological performance of the dosage forms is characterised by a low in vitro solvent extraction value for the opioid analgesic agents from the dosage forms and/or the absence of any significant effect upon absorption of opioid analgesic agents from the dosage forms when the dosage form is combined with alcohol. The controlled release carrier system may also be distinguished by unique pharmaceutical excipients such as solvents, carrier materials and network forerunners.
“An abuse-resistant oral pharmaceutical dosage form containing a pharmacologically active drug and a controlled release carrier is an additional object of the present invention. The controlled release carrier system allows for controlled in-vivo release of an agent. It is distinguished by the fact that the individual steady-state Cmin/Cmax variance during an interdose interval falls below or equal to the Therapeutic Index. Additionally, the carrier system contains a High Viscosity liquid carrier material (?HVLCM). A network former and at most one viscosity-enhancing agent. The present invention also aims to provide an abuse-resistant oral pharmaceutical dosage format that contains a pharmacologically active ingredient and a controlled-release carrier system. This dosage form can be used in a BID-dosing regime and further, the controlled-release carrier system may include a High Viscosity liquid carrier material (?HVLCM). A network former and at most one viscosity-enhancing agent. The invention also provides the above-described dosage forms in which the in vivo absorption is increased upon administration of dosage form with food or vice versa. The invention also provides the above-described dosage form whose in vivo pharmacological performance can be described by having an individual Cmin/Cmax variance of about 2 to 3. The invention also provides the above-described dosage formats where the controlled-release carrier system further reduces the risk of misuse and abuse. For example, the in vivo solvent extractability value for the active ingredient from the dosage forms is low and/or the lack of significant effects on absorption of active agent from dosage form when the dosage form is combined with alcohol. The controlled release carrier system may also be distinguished by unique pharmaceutical excipients that include certain combinations of solvents and viscosity-enhancing agents. Preferably, the active agent may be an opioid, CNS depressant, or CNS stimulant with a high potential for abuse or diversion. The active agent is preferred to be an opioid, amphetamine or methylphenidate. Each case can either be a salt, or a free base.
“It is also the object of this invention to provide an abuse resistant oral pharmaceutical dosage form that contains a pharmacologically active drug and a controlled-release carrier system. The controlled release carrier system allows for controlled in-vivo release of an agent. This is characterized by a steady state Cmin/Cmax variation that is less or equal to the Therapeutic Index. More specifically, this is a steady state Cmin/Cmax variation that is less or equal to 2 to 3. The present invention also aims to provide an abuse-resistant oral pharmaceutical dosage format that contains a pharmacologically active ingredient and a controlled-release carrier system. In particular, the individual Cmin/Cmax variance at steady state is less than or equal to about 2 to 3. The invention also provides the above-described dosage forms in which the in vivo absorption is increased upon administration of the dosage formula with food or where the in vivo release is substantially free of food effects. The invention also provides the above-described dosage forms in which the controlled release carrier system has a reduced risk of misuse and abuse. For example, the dosage forms are characterised by low in vitro solvent extraction values of the active agents and/or no significant effect on absorption by subjects of the dosage forms and alcohol. The controlled release carrier system may also be distinguished by unique pharmaceutical excipients that include certain combinations of solvents and viscosity-enhancing agents. Preferably, the active agent may be an opioid, CNS depressant, or CNS stimulant with a high potential for abuse or diversion. The active agent is preferred to be an opioid, amphetamine or methylphenidate. Each case can either be a salt, or a free base.
“The present invention also aims to provide an abuse-resistant oral pharmaceutical dosage format that contains a pharmacologically active ingredient and a controlled delivery carrier system. A High Viscosity Liquid Carrrier Material (?HVLCM?) is part of the controlled release carrier system. The controlled release carrier system includes a High Viscosity Liquid Carrier Material (?HVLCM?) and at least one viscosity-enhancing agent. The present invention also aims to provide dosage forms that enhance in vivo absorption from the dosage form when it is combined with food or where the in vivo release from the controlled-release carrier system is virtually free from any food effects. The invention also provides the above-described dosage forms in which the controlled release carrier system has a reduced risk of misuse and abuse. For example, the controlled release carrier system is low in vitro solvent extraction value and/or does not have any significant effect upon absorption of active agent from dosage form when the dosage form is combined with alcohol. The controlled release carrier system may also be distinguished by unique pharmaceutical excipients that include certain combinations of solvents and viscosity-enhancing agents. Preferably, the active agent may be an opioid, CNS depressant, or CNS stimulant with a high potential for abuse or diversion. The active agent is preferred to be an opioid, amphetamine or methylphenidate. Each case can either be a salt, or as a freebase.
“Another object of the invention is to provide an abuse resistant oral pharmaceutical dosage form that includes a pharmacologically active ingredient and a controlled-release carrier system. The carrier system is capable of providing at least 8 hours’ of substantially constant in vitro release when tested in an USP Type II dissolution apparatus with a stationary basket assembly. 20% or less of active agent can be extracted from the dosage form using EtOH (100 proof), as an extraction solvent at ambient temperature (RT) for one hour. The invention also provides an abuse-resistant oral pharmaceutical dosage format that includes a pharmacologically active ingredient and a controlled delivery carrier system. According to the invention, the carrier system provides at most 8 hours of substantially continuous in vitro release when tested in an USP Type II dissolution apparatus with a stationary basket assembly at 100 rpm and 0.1%N HCl dissolution medium containing surfactant. 30% or less of active agent can be extracted from the dosage form in an in vitro solvent extract test at ambient temperature (RT) for 1 hour
“It is another object of the invention that an oral pharmaceutical dosage form includes a drug agent and a controlled delivery carrier system. The controlled release carrier includes an HVLCM and a network foreman, a rheology modifier and a hydrophilic ingredient. The dosage form is also abuse-resistant. The invention also provides the described dosage form. However, the controlled release carrier system may include one or more of these additional components: a viscosity enhancer; solvent; and stabilizer agent. The HVLCM may include sucrose acetate butyrate (?SAM) in particular embodiments. The network former can include cellulose acetatebutyrate (?CAB?) The rheology modifier may include isopropyl myristate, (?IPM) The hydrophilic agent may contain hydroxyethylcellulose (?HEC?) The hydrophilic agent can contain hydroxyethyl cellulose (?HEC?). The active agent may contain an opioid as either a salt or a free base.
“It is an additional object of the invention that safer methods of treatment (including palliative) are provided to patients who require such treatment. These methods include administration of the abuse-resistant oral prescription dosage forms of this invention. The invention aims to provide a method for maintaining and establishing analgesia in a subject through repeated administration of an oral analgesic dose form. This dosage form is safe and can be used safely. In the instant method, the dosage form includes an analgesic and a controlled release carrier system. The controlled release carrier allows for controlled in-vivo release. This is characterized by a steady state Cmin/Cmax variation that is less or equal to the Therapeutic Index. The present invention also aims to provide a method of establishing and maintaining analgesia for a subject through repeated administration of an oral painkiller dosage form. This dosage form is safe and suitable for use in a BID dosing regimen. The invention also provides methods where the in vivo pharmaceutical performance of the dosage forms can be measured by having an individual Cmin/Cmax variance of about 2 to 3. The invention also provides methods wherein the in vivo pharmacological performance of dosage forms is reduced by having individual Cmin/Cmax variance at steady state that is less than or equal to about 2 to 3. A further object of this invention is to provide a method of maintaining and establishing analgesia in a subject through repeated administration of an abuse-resistant oral painkiller dosage form. This dosage form can be enhanced in that the bioavailability (e.g., in vivo absorption) of the analgesic agents is increased upon the co-administration with food. The methods include repeated administration of the dosage forms if the analgesic agent in question is an opioid. In a preferred embodiment, however, the opioid is in the dosage form in its base form.
“It is another object in the invention to provide a method of establishing and maintaining analgesia for a subject through repeated administration of an oral medication. The controlled release carrier includes an analgesic and analgesic agent. The controlled release carrier includes an HVLCM, an HVLCM, and at least one viscosity-enhancing agent. The dosage form is also safe and resistant to abuse, making it safer for patients. Another related object is to provide a method of establishing and maintaining analgesia for a subject through repeated administration of an oral painkiller dosage form. The dosage form also includes the described controlled release carrier system. This allows for controlled in-vivo release of analgesic agents. It is characterized by a steady state Cmin/Cmax variance that is less or equal to the Therapeutic Index. The present invention also aims to provide a method of establishing and maintaining analgesia for a subject through repeated administration of an oral painkiller dosage form. This dosage form can be used in a BID-dosing regimen. The invention also provides methods where the in vivo pharmaceutical performance of the dosage forms can be measured by having an individual Cmin/Cmax variance of about 2 to 3. The invention also provides methods wherein the in vivo pharmacological performance of dosage forms is reduced by having individual Cmin/Cmax variance at steady state that is less than or equal to about 2 to 3. A further object of this invention is to provide a method of maintaining and establishing analgesia in a subject through repeated administration of an abuse-resistant oral painkiller dosage form. This dosage form can be enhanced in that the bioavailability (i.e., in vivo absorption) of the analgesic agents is increased upon the co-administration with food. The methods include repeated administration of the dosage forms if the analgesic agent in question is an opioid. In a preferred embodiment, however, the opioid is in the dosage form in its base form.
The present invention has the advantage that abuse-resistant oral dosage forms can provide enhanced safety features and/or misuse-resistance qualities, in addition to improved in-vivo pharmacological performances. The invention also has the advantage that inventive dosage forms are easy to construct and can be used to offer a wider range of safer and more effective pharmacological solutions for the medical field.
“These and other aspects, advantages and objects of the invention will be readily apparent to the skilled person after reading the instant disclosure.
“POINTS ON THE INVENTION”
“1. “1. A controlled release pharmaceutical dosage form that contains a pharmacologically active drug and a controlled delivery carrier system. It includes:
“2. “2.
“3. “3.
“4. “4.
“5. “5.
“6. “6.
“7. “7.
“8. “8.
“9. “9.
“10. “10.
“11. “11.
“12. “12.
“13. “13.
“14. “14.
“15. “15.
“16. “16.
“17. “17.
“18. “18.
“19. “19.
“20. “20.
“21. “21.
“23. “23.
“24. The dosage form of point 23, wherein the capsule comprises gelatin, hydroxyethylcellulose or hydroxypropylmethylcellulose.”
“25. “25.
“26. “26.
“27. “27.
“28. “28.
“29. “29.
“30. A form of oral pharmaceutical dosage that can be obtained by following the process described in points 26-29.
“31. “31.
“32. “32.
“33. “33.
“34. “34.
“35. “35.
“36. “36.
“37. “37.
“38. “38.
“39. “39.
“40. “40.
“41. “41.
“42. “42.
“43. “43.
“44. “44.
“45. “45.
“46. “46.
“47. “47.
“48. Point 46 is the dosage form, in which individual Cmin/Cmax variations at steady state are less than or equals to 2 to 3.
“49. Point 46 is the dosage form that can be used in a BID-dosing program.
“50. Point 46 is the dosage form in which the active agent is an opioid.
“51. Point 46. The dosage form in which the active agent is given as a free base.
“52. “52.
“53. “53.
“54. “54.
“55. “55.
“56. “56.
“57. “57.
“58. “58.
“59. “59.
“60. “60.
“61. Method to increase the oral bioavailability and effectiveness of active agents to subjects receiving treatment with them. This method involves orally administering the dosage form described at point 46 to the subject with food.
“62. Method to increase the absorption of active agents from oral dosage forms. This method involves orally administering to the subject dosage form 46 along with food.
“63. “63.
“64. “64.
“65. “65.
“66. “66.
“67. “67.
“68. “68.
“69. “69.
“70. “70.
Click here to view the patent on Google Patents.