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( 12 ) United States Patent US010004749B2 (12 ) United States Patent ( 10 ) Patent No. : US 10 , 004, 749 B2 Hsu (45 ) Date of Patent: Jun . 26 , 2018 ( 54 ) COMPOSITION COMPRISING A ( 56 ) References Cited THERAPEUTIC AGENT AND A RESPIRATORY STIMULANT AND U . S . PATENT DOCUMENTS METHODS FOR THE USE THEREOF 2002 / 0010127 A1 * 1/ 2002 Oshlack A61K 9 /0031 424 / 449 ( 71 ) Applicant : John Hsu , Rowland Heights , CA (US ) 2003 /0092701 A1 * 5 /2003 Lalley .. .. .. A61K 31/ 4745 514 /217 .02 2012 /0100107 A1 4 /2012 Mannion et al . (72 ) Inventor : John Hsu , Rowland Heights , CA (US ) 2012 /0270848 A1 10 /2012 Mannion et al. ( * ) Notice : Subject to any disclaimer , the term of this 2014 / 0030322 Al 1 / 2014 Bosse et al . patent is extended or adjusted under 35 2015 /0291597 Al 10 /2015 Mannion et al. U . S . C . 154 (b ) by 0 days. days . OTHER PUBLICATIONS (21 ) Appl . No. : 15/ 214 , 421 International Search Report and Written Opinion , PCT /US2016 / 043024 , dated Sep . 26 , 2016 . Jul. 19 , 2016 Randall , et al . , Effect of oral doaxapram on morphine induced ( 22 ) Filed : changes in the ventilatory response to carbon dioxide , Br. J Anaest , vol. 62 , 1989 , 159 - 163 . (65 ) Prior Publication Data Robson , A pharmacokinetic study of doxapram in patients and US 2017 /0020885 A1 Jan . 26 , 2017 volunteers, Br. J. Clinical Pharmac. , 1978 , vol. 7 , 81 -87 . * cited by examiner Related U . S . Application Data Primary Examiner — Bethany P Barham Assistant Examiner — Barbara S Frazier (60 ) Provisional application No . 62 / 195 ,769 , filed on Jul. ( 74 ) Attorney , Agent, or Firm — Entralta P . C . ; James W . 22 , 2015 . Collett ; Peter D . Weinstein ( 51 ) Int . Ci. ( 57 ) ABSTRACT A61K 31 /5377 (2006 .01 ) The present disclosure provides a safe method for anesthesia A61K 31/ 485 ( 2006 . 01 ) or the treatment of pain by safely administering an amount A61K 45 / 06 ( 2006 . 01 ) of active agent to a patient while reducing the incidence or severity of suppressed respiration . The present disclosure A61K 9 / 00 ( 2006 .01 ) provides a pharmaceutical composition comprising a thera A61K 9 / 24 ( 2006 . 01 ) peutic agent and a chemoreceptor respiratory stimulant. In A61K 9 /50 ( 2006 .01 ) one aspect , the compositions oppose effects of respiratory (52 ) U .S . CI. suppressants by combining a chemoreceptor respiratory CPC .. .. .. A61K 31 /5377 ( 2013 .01 ) ; A61K 9 / 0019 stimulant with an opioid receptor agonist or other respira (2013 .01 ) ; A61K 9 / 0053 ( 2013 .01 ) ; A61K tory - depressing drug . The combination of the two chemical 9 /209 (2013 .01 ) ; A61K 9 /5047 ( 2013 .01 ) ; agents , that is , the therapeutic agent and the respiratory A61K 9 /5073 ( 2013 .01 ) ; A61K 31/ 485 stimulant, may be herein described as the “ drugs .” The ( 2013 . 01 ) ; A61K 45 / 06 ( 2013 . 01 ) present compositions may be used to treat acute and chronic (58 ) Field of Classification Search pain , sleep apnea , and other conditions, leaving only non None lethal side effects . See application file for complete search history . 12 Claims, No Drawings US 10 , 004 , 749 B2 COMPOSITION COMPRISING A November 2014 issue of the journal Pain found an increased THERAPEUTIC AGENT AND A risk of death associated in patients with chronic pain pre RESPIRATORY STIMULANT AND scribed opioids for long- term use while a somewhat lower METHODS FOR THE USE THEREOF risk was associated with short- term use . 5 The increased availability of opioids was partially brought BACKGROUND OF THE INVENTION about by The Joint Commission On Accreditation of Health Certain pharmaceutical drugs are known to suppress care Organizations ( ICAHO ) standards from 2000 that respiration . Of those pharmaceutical drugs , opioid receptor demands pain be addressed by healthcare providers as the agonists ( also described herein as either “ opioids” or “ nar- 10 fifth vital sign . The evaluation of pain was thus made cotics ” ) are the most well - known . equivalent to the evaluation of a patient' s vital signs includ Most often , opioids are currently used to treat pain . ing the heartbeat , blood pressure , respiratory rate , and tem Opioids are potent analgesics and they are prescribed for perature . A 2012 study showed that physicians played an patients in pain who need powerful painkillers . Acute pain , important role in prescription drug overdoses as they ( for example , pain in duration of less than three months ) , is 15 attempted to comply with Federalmandates , avoid malprac treated most often with short acting immediate release tice claims, avoid decreased patient satisfaction scores ( as opioid medications, while chronic pain , ( for example , pain patients began demandingmore prescriptions for opioid pain in duration of greater than three months ), is treated often medications) , and avoid decreased reimbursement . The with long acting or extended release formulations of opioid same study found that of 3 ,733 fatalities associated with medications . 20 prescription opioid drugs, the drugs that caused or contrib Chronic nonmalignant pain is a silent epidemic in the U . S . uted to nearly half of the deaths were prescribed to patients that affects approximately 116 million Americans. Patients by physicians. This public health issue confounds the clini who take opioids for an extended period , can develop a cal utility of opioids . The extent of their efficacy in the tolerance and require higher and higher doses of the drugs, treatment of pain when utilized on a chronic basis has not increasing the risk of overdose and other problems. It is also 25 been definitively proven and has made long -term treatment the most common reason patients seek medical care , result of non - cancer pain with opioids controversial . Coupled with ing in $ 635 billion annually in both medical costs and the abuse and addiction potential, clinical safety concerns decreased work productivity . Although the physiology of and side effect profile , proper physician prescribing of chronic pain continues to be poorly understood , it has been opioids may be prevented , and result in inadequate pain identified as a disorder associated with many psychosocial 30 management . conditions , including lack of appetite , depression , and sleep Though the bulk of the current research is focused on disturbances. abuse deterrence , addiction avoidance and patient safety , Opioids have well -known pharmacodynamic profiles prescription drug are still abused , overdoses occur and death associated with a significant number of side effects and rates continue to rise. It is apparent that this approach is not complications . Common side effects of opioid administra - 35 successful in preventing patient deaths . The abuse deterrent tion include sedation , dizziness , nausea , vomiting , and con - developments have either been too difficult to manufacture stipation . Less common side effects may include delayed or fail in clinical use . “ Mu receptor Modulation " has not gastric emptying, hyperalgesia , immunologic and hormonal worked . A different approach must to be tried to save patient dysfunction , infertility ,muscle rigidity , myoclonus , physical lives. Presently , as abuse deterrence technologies are devel dependence , tolerance , respiratory depression , respiratory 40 oped , narcotic abusers and addicts quickly discover innova arrest and death . Painkiller deaths quadrupled between 1999 tive methods to achieve their goal of reaching a euphoric and 2011 , mirroring a sharp rise in the number of prescrip - " high ” . They crush drugs, intravenously inject drugs , snort tions for such drugs. In 2009 , overdoses involving painkill drugs, extract drugs with alcohol or combine multiple drugs ers pushed drug fatalities past traffic accidents as a cause of to defeat pharmaceutical abuse deterrence technology as death . In 2011 the U . S . Centers for Disease Control and 45 they are developed . It is a cycle that has led to many deaths . Prevention declared prescription opioid abuse an epidemic . The CDC determined that abuse of prescription opioid drugs Well -known complications of opioids include the phe - is an epidemic because it has led to a quadrupling of death nomenon of both physical and psychological dependence rates in recent years . Rethinking of the method in which pain and addiction , which can in turn lead to opioid misuse , abuse is treated with opioids must be done . The current trend to use and diversion . More than 70 % of the illegal users obtain 50 multimodal pain therapy, which utilizes non - narcotics in opioids by stealing them during pharmacy robberies , pur - synergy to treat pain is a step in the right direction . Unfor chasing them illegally on the black market, or receiving tunately , in clinical practice this has been implemented by them from family or friends. These individuals seek to only about 30 percent of physicians in the country . Rethink achieve a “ high ” from prescription medications by taking an ing of the method in which opioids are used to treat pain excess number of pills orally or by crushing the pills , 55 must also be done . There is an epidemic of prescription drug followed by snorting , smoking , or injecting the new altered abuse and it is getting worse despite efforts to solve it . More formulation . The misuse or abuse of prescription opioid opioid pain medications are prescribed today than ever medications is a growing problem , with abuse rates having before because of Federal JCAHO regulations mandating quadrupled in the decade from 1990 to 2000 . The deaths the treatment of pain . The
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