.
`
`United States Patent [191
`Stanley et al.
`
`llllllllllllllIlllllllllllllllllllllllllllllll|||||Illllllllllllllllllllll
`[11] Patent Number:
`5,288,497
`[451 Date of Patent: * Feb. 22, 1994
`
`US005288497A
`
`[54] COMPOSITIONS OF ORAL DISSOLVABLE
`MEDICAMENTS
`[75] Inventors: Theodore H. Stanley, Salt Lake City;
`Brian Hague, West Valley City, both
`of Utah
`[73] Assignee: The University of Utah, Salt Lake
`City, Utah
`The portion of the term of this patent
`subsequent to Sep. 5, 2006 has been
`disclaimed.
`[21] Appl. No.: 403,751
`[22] Filed:
`Sep. 5, 1989
`
`[ ' ] Notice:
`
`[63]
`
`Related US. Application Data
`Continuation-impart of Ser. No. 60,045, Jun. 8, 1987,
`Pat. No. 4,863,737, which is a continuation-in-part of
`Ser. No. 729,301, May 1, 1985, Pat. No. 4,671,953.
`
`[51] Int. Cl.5 .............................................. .. A61K 9/68
`[52] US. Cl. .... ..
`.
`.. 424/440; 424/441;
`424/435; 424/434; 424/484
`[58] Field of Search ............. .. 424/440, 441, 484, 434,
`424/435
`
`[56]
`
`References Cited
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`
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`2,246,778 6/1941 Cahoon
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`..... .. 43/34
`
`2,323,656 7/1943 Helfenstein . . . . . . . . . .
`
`. . . . . .. 43/36
`
`2,388,533 11/1945 Edmondson et a1.
`
`.. 128/202
`
`2,469,589 5/ 1949 Barricini . . . . . . . . . . . . . .
`
`. . . .. 99/ 138
`
`2,488,272 11/1949 Davis . . . . . . . . . . . . . . . . . . .
`
`. . . .. 57/154
`
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`2,508,560 5/1950 Adams .......................... .. 43/36
`2,553,446 5/1951 Edmondson et a1.
`128/188
`2,857,908 10/1958 Corn?eld .................... .. 128/ 15
`2,897,624 8/1959 Yakel et a1. ............ ..
`43/36
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`128/188
`2,926,121 2/1960 Hobbs et a1. ...................... .. 424/440
`(List continued on next page.)
`
`FOREIGN PATENT DOCUMENTS
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`132404 9/ 1978 German Democratic Rep. .
`1083896 9/1967 United Kingdom .
`1171691 11/1969 United Kingdom .
`
`OTHER PUBLICATIONS
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`Mucous Membrane”, 196 The Practitioner 125 (1966).
`(List continued on next page.) '
`
`Primary Examiner-Paul R. Michl
`Assistant Examiner—-Raj Bawa
`Attorney, Agent, or Firm-Workman Nydegger &
`Jensen
`ABSTRACT
`[57]
`Compositions and methods of manufacture for produc
`ing a medicament composition capable of absorption
`through the mucosal tissues of the mouth, pharynx, and
`esophagus. The present invention relates to such com
`positions and methods which are useful in administering
`lipophilic and nonlipophilic drugs in a dose-to-effect
`manner that sufficient drug is administered to produce
`precisely a desired effect. The invention also relates to
`a manufacturing technique that enables a therapeutic
`agent or drug to be incorporated into a ?avored dissolv
`able matrix. An appliance or holder is preferably at
`tached to the dissolvable matrix. Employing the present
`invention the drug may be introduced into the patient’s
`bloodstream almost as fast as through injection, and
`much faster than using the oral administration route,
`while avoiding the negative aspects of both of these
`methods. The present invention achieves these advan
`tages by incorporating the drug into a carbohydrate, fat,
`protein, wax, or other dissolvable matrix composition.
`The dissolvable matrix may include permeation enhanc
`ers to increase the drug absorption by the mucosal tis
`sues of the mouth. The matrix composition may also
`include pH buffering agents to modify the salival pH
`thereby increasing the absorption of the drug through
`the mucosal tissue.
`
`219 Claims, 2 Drawing Sheets
`
`TEVA EXHIBIT 1022
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`
`

`
`5,288,497
`Page 2
`
`us. PATENT DOCUMENTS
`2,963,404 12/1960 Hammer =1 al. .................... .. 167/82
`3,114,64212/1963 Meisel ........... ..
`3,169,907 2/1965 Heusser =1 al. ............... .. 424/440x
`3,172,179 3/1965 561mm ................................. .. 24/91
`3,192,924 7/ 1965 Edmondson et al.
`.. 128/188
`3,210,247 10/1965 Suranyi ............. ..
`514/270
`3,264,115 3/1966 Davis
`99/138
`3,271,256 9/1966 Frey .................. ..
`167/82
`3,341,414 9/1967 (2111811163 etal.
`167/82
`3,344,030 9/1967 Stevens et 111- -~
`514/270 X
`1;;
`3;“ c‘ 31- - ~ ~ - -
`~ ~ - ~- 128/133
`Wm“
`------- -- ‘3/35
`1
`'
`3,429,308 2/1969 Russell ....... ..
`424/440x
`3,438 787 4/1969 Du Ross _ . . . . .
`. . . . . .. 99/134
`3,493,652 2/1970 Hartman ..
`424/435x
`3,556,811 1/1971 51111111 . . . . . . .
`. . . . . .. 99/134
`3,738,845 6/1973 Liebrand ..
`99/134 R
`3,797,494 3/1974 Zaffaroni .
`128/268
`3,816,953 6/1974 Hameen-Anttila .
`43/35
`3,867,927 2/1975 HCIZgOI't ............. ..
`128/15
`3,943,928 3/1976 Lanccla etal
`128/260
`.
`3,996,934 12/1976 2311616111 ................. ..
`
`4,060,084 11/1977 Chandraseltaran =1 al. 4,093,709 6/1978 ch61 =1 al. ................ ..
`4,131,648 12/1978 ChOi =1 al.
`4,l38,344 2/1979 Choi et a1.
`
`128/268
`
`128/260 424/19
`424/22
`252/1
`
`4,749,575 6/1988 Rotman ............................. .. 424/441
`‘1764378 8/‘983
`24 440
`418181539 4/1989
`‘18631737 9/1989 sum!” “*‘1' """"""""""""" " ‘ /
`1 N5
`QTHER PUBLICCAT O .
`Bwk‘“ ‘F‘ a!" Bmical AbsPrPm“ °f B851‘: Drugs and
`Its App11cat1on as an In V1vo Model of Pass1ve Drug
`Transfer Through Lipid Membranes,” 19 J. Pharm
`Pharmac, 31S (1967).
`Dearden et al., “Buccal Absorption as a Parameter of
`Analgesic Activity of Some P-Substituted Acetani~
`111163,” 23 161111161 Pharm. Pharmac. 73s (1971).
`,.
`,.
`r
`Dearde“ e‘ “1" A New Buccal Absorpt‘on Model’ 23
`J- Pharm' PhmaFa 68s(1?71)-
`_
`Dollcry 9t 41-, “Drfferenccs 1n the Metabohsm of Drugs
`Depending Upon Their Routes of Administration,” 179
`Annals of the New York Academy of Sciences 108
`(1971),
`Dobkin’ “Buprcnorphine Hydrochloridcz Detennina_
`-
`-
`.,
`-
`~
`tion of Analgesic Potency, 24 Canadian Anaesthes1
`.
`.~
`
`, °1°3Y Sway hum“) 186 (1977) Edge 91 81-, “Analseslc Effects 01" Sublmgual Buprenof
`
`phine,” 34 Anaesthesia 463 (1979)
`Fry, “Relief of Pain After Surgery,” 34 Anaesthesia 549
`
`4,139,627 2/1979 Lane =1 a], . . . . . .
`
`. . . .. 424/267
`
`(1979)_
`
`13/
`
`:"f?md e‘ 111
`
`a” et a1‘ ' ' ' ' ' ' '
`l
`‘
`'
`4,225,627 9/1980 Moore . . . . . . . . .
`4,226,848 10/1980 Nagai =1 111..
`4,241,092 12/1980 1161111 =1 al. ..
`4,292,299 9/1981 Suzuki =1 al.
`4,307,075 12/1981 Martin .... ..
`4,311,722 6/ 1982 Vinlf ct al-
`4,335,147 6/1992 Soll1cl1 . _ . . .
`45461709 8/1982 $911191"
`4,372,942 2/1983 C1m1luca..
`4,390,520 6/1983 Nagai =1 111..
`4,452,825 6/1984 Khcik ct al.
`4,466,953 3/1984 Keith C, a]. “
`4,470,962 9/1984 1<=1111 =1 al. ..
`4,482,534 11/1984 Blank ......... ..
`4,485,087 11/1984 01511113 =1 al.
`4,517,173 5/1985 Ktzawa et al. . . . . . ,
`4,529,589 7/1985 Davydov =1 al.
`
`514/2707‘
`
`Bullingham et al., "Sublingual Buprenorphine Used
`
`' ' ' " 424/435
`. . . .. 426/548
`424/440x
`..... .. 426/96
`424/440x
`424/28
`426/660
`. . . .. 426/295
`‘28/260
`424/16
`424/28
`426/658
`424/28
`424/28
`424/28
`424/28
`. . . .. 424/435
`424/440):
`
`Postoperatively: Clinical Observations and Preliminary
`Ph
`ki
`. A a1 .
`,, 12 B J Cl. Pb
`“mam “cm “ ys‘s’
`1"
`'
`1"‘
`armac‘
`_
`_
`117 (1931)
`Plug 91 41-, "The Pharmacokmencs 0f Fentanyl,”
`Janssen Pharmaceutical, Inc. (1981).
`Ellis et al., “Pain Relief After Abdominal Surgery-A
`Comparison of LM. Morphine, Sublingual Buprenor
`P1111113 and self-14111110116161 1.v. 189111111116," 54 Br. J.
`Anacsth 421 (1982)
`'
`u
`'
`.
`.
`.
`,,
`Port et al., Carfentaml: The Primate Expenence,
`Amencan College of Veterinary Anesthesiologist
`(1983).
`Port et al., “Topical Narcotic Anesthesia,” to Anesthe
`si01Ogy(1933)_
`windholz et 31" “The Merck Index,” published by
`Merck & Co Inc
`575 795 796 and A ndix 3
`
`'-
`
`. . . 1424/4140
`4,551,329 11/1985 Harris =1 al. . . . . . . . .
`424/440x
`4,572,832 2/1986 Kigasawa =1 al.
`4,588,580 5/1986 Gale =1 al. ....................... .. 424/21
`4,671,953 6/1987 Stanley =1 al. ........... ..
`.424/440
`4,695,463 9/1987 Yang =1 al ........................ .. 424/440
`
`"
`
`’
`" PP'
`_
`_
`,
`(1983)‘
`Abrams, “New Nltme Dellvcry System-S” Buccal N1
`troglycerin, vol- 105 American Heart Journal, pp
`848-854 (May 1983).
`
`*
`
`’
`
`Ppe
`
`TEVA EXHIBIT 1022
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
`5,288,497
`Page 3
`
`OTHER PUBLICATIONS
`
`White et al., “Comparative Pharmacology of Intrave
`nous Anesthetics-A Model for Determining Dosage
`Requirements and Therapeutic Concentration Ranges
`During Surgery,” 59 Anesthesiology, A379 (Sep. 1983).
`Asthana et al., “Verapamil Disposition and Effect on
`PQ-Intervals After Buccal, Oral and Intravenous Ad
`ministration,” Arzneim.-Forsch./Drug Res, pp.
`498-502 (1984).
`Derbyshire et al., “Non-Parenteral Postoperative Anal
`gesia,” Anesthesia 39, pp. 324-328 (1984).
`DeBoer et al., “Drug Absorption by Sublingual and
`Rectal Routes,” 56 British Journal of Anaesthesiology
`69 (1984).
`Stanley et al., “The Effect of Population Habits on Side
`Effects and Narcotic Requirements During High-Dose
`Fentanyl Anaesthesia,” 31 Can Anaesth Soc J 3987
`(1984).
`Bailey et al., “Anesthetic Induction with Fentanyl,” 64
`Anesthe Analg ( 1985).
`Stanley et al., “Management of Pain and Pain-Related
`Problems in the Critically Ill Patient,” in Critical Care,
`State of the Art, vol. 6 (1985).
`Huttel et al., “Sublingual Flunitrazepam for Premedica
`tion," Acta Anaesthesiol Scand. 29, pp. 209-211 (1985).
`Risbo et al., “Sublingual Buprenorphine for Premedica
`tion and Postoperative Pain Relief in Orthopedic Sur
`gery,” Acta Anaesthesiol Scand. 29, pp. 180-182 (1985).
`Bell et al., “Buccal Morphine-A New Route for Anal
`_ gesia?” The Lancet 71 (1985).
`Berry, “Premedication and Induction of the Difficult
`Child" (n.d.).
`John D. Ryan, “Premedication, Induction and Pa
`rents,”Newsletter Boston, Mass. (n.d.).
`“Sublimize (fentanyl) as the Citrate Injection” Product
`Information (n.d.).
`__
`Stanley, “Computer Control of Intravenous Anesthe
`sia,” 423.
`Schechter et al., “Status of Pediatric Pain Control: A
`
`Comparison of Hospital Analgesic Usage in Children
`and Adults,” 77 Pediatrics 11 (186).
`Prys-Roberts et al., “Pharmacokinetics of Anaesthe
`sia,” Preface.
`Bailey et al., “Pharmacology of Intravenous Narcotic
`Anesthetics,” in Anesthesia 2nd ed. (Miller ed. 1986).
`Su, “Intranasal Delivery of Peptides and Proteins,”
`Pharmacy International (Jan. 1986).
`Rothschild, “Are Sick Kids Treated Properly for
`Pain?” USA Today, Jan. 28, 1986.
`Forbes et al., “2% Rectal Methohexital for Induction of
`Anesthesia in Children,” vol. 65 Anesthesiology No. 3
`(Sep. 1986).
`Newspaper article entitled “Insulin Shots May Soon be
`Replaced by a Nasal Spray,” Friday, Sep. 26, 1986
`(UPI).
`“New Drugs/Drug News,” Hospital Therapy, pp. 9,
`10, and 15 (Nov. 1986).
`’
`Davis, “Parenteral Therapy Techniques-Abstracts,”
`Hospital Pharmacy, vol. 21, pp. 1171-1178 (Dec. 1986).
`“Personalized Dosing and Effective Drugs can Control
`Emesis,” Pharmacy Practice News, p. 11 (Mar. 1987).
`“Administration of Drugs by the Buccal Route,” The
`Lancet, pp. 666-667 (Mar. 21, 1987).
`Lee, “Ophthalmic Delivery of Peptides and Proteins,”
`Pharmaceutical Technology, pp. 26-38 (Apr. 1987).
`Mecklenburg, “Insulin Pump Therapy 1987," Practice
`Diabetology, vol. 6, No. 2, pp. l-7 (Mar./Apr. 1987).
`Grover et al., “Low-does Intranasal Nitroglycerine
`Attenuates Pressor Response,” 66 Anesthesiology, p.
`722 (1987).
`Oyama, Opioids in Anesthesia, Chapter 13: “Effects of
`Intrathecal and Epidural Morphine on Endocrine Func
`tion".
`McLeskey, Opioids in Anesthesia, Chapter 20: “Con
`tinuous-Infusion Alfentanil for Surgical Anesthesia”.
`Kitahata, Opioids in Anesthesia, Chapter 28: “Intra
`thecal and Epidural Short-Acting Narcotics.”
`
`TEVA EXHIBIT 1022
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
`US. Patent
`
`Feb. 22, 1994
`
`Sheet 1 of 2
`
`5,288,497
`
`TEVA EXHIBIT 1022
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`
`

`
`US. Patent
`
`Feb. 22, 1994
`
`Sheet 2 of 2
`
`5,288,497
`
`TEVA EXHIBIT 1022
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
`1
`
`5
`
`COMPOSITIONS OF ORAL DISSOLVABLE
`MEDICAMENTS
`This application is a continuation-in-part application
`of copending application Ser. No. 07/060,045, ?led Jun.
`8, 1987, in the names of Theodore H. Stanley, MD. and
`Brian Hague and entitled “COMPOSITIONS AND
`METHODS OF MANUFACTURE OF COM
`PRESSED POWDER MEDICAMENTS,” now US.
`Pat. No. 4,863,737 which issued Sep. 5, 1989, which is a‘
`continuation-in-part of US. application Ser. No.
`06/729,301, ?led May 1, 1985, and entitled “METH
`ODS AND COMPOSITION FOR NONINVASIVE
`ADMINISTRATION OF SEDATIVES, ANALGE
`SICS, AND ANESTHETICS,” now US. Pat. No. ‘
`4,671,953 which issued Jun. 9, 1987 in the names of
`Theodore H. Stanley and Brian Hague.
`!
`BACKGROUND
`1. The Field of the Invention
`The present invention relates to compositions and
`methods of manufacture of oral dissolvable matrixes for
`medicaments used in the buccal, sublingual, pharyngeal,
`and esophageal transmucosal delivery of the medica
`ments. More particularly, the present invention is di
`rected to compositions, and methods and apparatus for
`producing such compositions, for noninvasive adminis
`tration of dose-to-effect amounts of medicaments
`through the mucosal tissues of the mouth, pharynx, and
`esophagus.
`2. Related Applications
`That application and patent are incorporated herein
`by speci?c reference.
`THE BACKGROUND OF THE INVENTION
`Recently, numerous advancements have taken place
`in the ?eld of pharmacology and pharmaceutics with
`respect to the administration of drugs to treat various
`conditions. Despite the tremendous advancements in
`the ?eld, however, drugs continue to be administered
`using substantially the same techniques that have been
`used for many decades. The vast majority of pharma
`ceutical agents continue to be administered either orally
`or by injection. Nevertheless, it is frequently found in
`the art that neither of these administration routes are
`effective in all cases, and both administration routes
`suffer from several disadvantages.
`Oral administration is probably the most prevalent
`method of administering pharmacological medica
`ments. The medicament is generally incorporated into a
`tablet, capsule, or a liquid base, and then swallowed.
`The oral administration modality is often preferred
`because of its convenience. In addition, oral administra
`tion is generally nonthreatening, painless, and simple to
`accomplish for most patients.
`Nevertheless, oral administration of drugs suffers
`from several disadvantages. One disadvantage is that
`pediatric and geriatric patients frequently have dif?
`culty swallowing pills and other solid dosage-forms,
`and such patients often refuse to cooperate in swallow
`ing a liquid medication. In addition, for many medica
`ments, the act of swallowing the medicament often
`requires ?uids and increases gastric volume and the
`likelihood of nausea and vomiting.
`A further problem with oral administration is that the
`rate of absorption of the drug into the bloodstream after
`_ swallowing varies from patient to patient. The absorp
`tion of the drug is dependent upon the movement of the
`
`5,288,497
`2
`drug from the stomach to the small and large intestines
`and the effects of secretions from these organs and on
`the resulting pH within the stomach and intestines.
`Anxiety and stress can dramatically reduce these move
`ments and secretions, prevent or reduce the ?nal effects
`of the drug, and delay onset of the drug’s effects.
`Most signi?cant is the fact that there is normally a
`substantial delay between the time of oral administra
`tion and the time that the therapeutic effect of the drug
`begins. As mentioned above, the drug must pass
`through the gastrointestinal system in order to enter the
`bloodstream; this typically takes forty-?ve minutes or
`longer. As mentioned above, anxiety and stress often
`increase this delay.
`For many applications, such as premedication before
`surgery or where immediate relief from pain or a serious
`medical condition or immediate effectiveness of the
`drug is required, this delay is unacceptable. In modern
`outpatient units and operating rooms where rapid turn
`over of patients is essential for cost containment, exten
`sive delays in the action of a drug are simply unaccept
`able.
`An additional disadvantage of oral administration is
`that many drugs almost immediately experience metab
`olism or inactivation. The veins from the stomach and
`the small and large intestines pass directly through the
`liver. Thus, drugs entering the bloodstream must ?rst
`pass through the liver before distribution into the gen
`eral blood circulation. More than sixty percent of most
`drugs (and essentially one hundred percent of certain
`drugs) are removed from the patient’s bloodstream
`during this “?rst pass” through the liver. The result is
`that oral administration is impractical for many drugs,
`particularly many central nervous system and many
`cardiovascular-acting drugs that are used for rapid
`onset in critical care situations, as a premedication prior
`to surgery, or for the induction of anesthesia.
`Further, additional stress is placed on the liver as it
`removes the excess drug from the bloodstream. This is
`particularly severe if the drug treatment has been occur
`ring over an extended period of time. The liver may
`become overloaded with the drug’s metabolite which
`then must be excreted. As a result, there is an increased
`risk of hepatic or renal disorders.
`Another dif?culty encountered in administering
`drugs orally is that dosages are prepared or determined
`for use with an “average” patient. Most drugs have
`widely varying effects on different patients. These ef
`fects depend upon patient habits,_subtle genetic differ
`ences between patients, blood volumes, age, and numer
`ous other known and unknown factors. Introducing a
`bolus of drug orally does not provide the ability to
`control the precise dose needed to obtain the desired
`effect, rather the dose is estimated in order to produce
`an average effect in an average patient. The result may
`be underdosing or overdosing a particular patient.
`Underdosing a patient because of a low susceptibility
`to the drug fails to evoke the response sought by the
`physician. Overdosing the patient can result in danger
`ous depression of vital body functions, especially the
`heart and lungs. This can cause prolonged respiratory
`depression (necessitating mechanical ventilation after
`surgery), cardiac depression, and cardiac arrest.
`In order to avoid some of the disadvantages of oral
`administration, injection is frequently used. Injecting a
`drug (generally intravenously or intramuscularly), re
`sults in rapid entry of the drug into the patient’s blood
`stream. In addition, this type of delivery avoids the
`
`15
`
`20
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`25
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`30
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`35
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`40
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`55
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`60
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`5,288,497
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`4
`removal’. of large quantities of the drug by the patient’s
`hot candy mass may be poured into molds, the size and
`shape of which may be determined as desired.
`liver. As a result, less total drug is usually needed com
`For effective application of the drug, the ?nal candy
`pared to orally distributed to various portions of the
`product may contain the drug uniformly distributed
`patient’s body before exposure to the liver.
`Most patients, particularly children and geriatric
`throughout in order to ensure uniform levels of medica
`tion. Alternatively, for some applications, varying con
`adults, have an aversion to injections. In some patients,
`centrations within known and controlled ranges may be
`this aversion may be so pronounced as to make the use
`desired to vary the rate of drug administration. Difficul
`of injections a serious concern. Since intense psycholog
`ties are encountered in attempting to blend solid drugs
`ical stress can exacerbate a patient’s debilitated condi
`in a uniform or otherwise carefully controlled manner.
`tion, it sometimes becomes undesirable to use injections
`Many drugs are insoluble, or only partially soluble, in
`where the patient is seriously ill or suffers from a debili
`one or more of the ingredients of the hard candy base.
`tating condition or injury.
`Thus, the resultant product is often found to be lacking
`In addition, individual variations in susceptibility in
`in uniform or controlled distribution of the drug.
`the metabolism of various drugs (particularly drugs
`In addition, it is often found that when the tempera
`with central nervous system activity) are even more
`ture of the candy mass is increased in order to enable a
`profound when utilizing the injection route. In many
`more uniform distribution (generally to a temperature
`‘instances to prevent overdosing, it is the practice to
`above approximately 230° C.), considerable decomposi
`inject a patient with a lower than average dose and then
`tion of the drug takes place. While the extent of decom
`supplement the dose with additional injections as neces
`position may vary, high temperatures are generally
`sary. This “titration” makes necessary the use of re
`undesirable in the handling and processing of medica
`peated injections, which in turn greatly increases stress
`tions. Thus, the process of formation of the candy prod
`on the patient. Again, a precise dose cannot be adminis
`uct may itself degrade and/or inactivate the therapeutic
`tered to produce a precise effect because the patient’s
`agent.
`response varies widely depending on the speci?c char
`Furthermore, many presently available medicated
`acteristics of the speci?c patient.
`candy lozenges tend to crumble when placed in the
`One common approach to preparing a patient for
`mouth. As a result, uniform release of the drug into the
`surgery is to orally administer a sedative or anxiolytic.
`mucosal tissues does not take place. Rather, the crum
`Although quick onset of sedation or anxiolysis has not
`bled lozenge is mostly chewed, and swallowed, and the
`always been a critical factor, it is more so now. Chang
`drug enters the bloodstream through the stomach and
`ing practices, including the increased use of outpatient
`intestines as described above. Thus, it will be appreci
`units for day surgery and the pressures for cost contain
`ated that candy lozenges have very definite limitations
`ment in modern medicine, dictate rapid onset of action
`for use in the administration of a drug through the oral
`and the use of an absolutely ideal dose in order to avoid
`mucosal tissues. As a result, lozenges have not been
`increased costs of caring for patients with delayed re
`used to administer potent, fast-acting drugs, such as
`covery secondary to slightly overdosing with anesthe
`drugs that affect the central nervous system, the cardio
`sia. Effective oral administration of premedication
`vascular system, or the renal vascular system.
`drugs with central nervous system activity (which
`While the administration of certain drugs through the
`cause a rapid onset of sedation and anxiolysis without
`oral mucosal tissues has shown promise, development
`producing excessive sedation) is often difficult to ac
`of a fully acceptable method for producing a medication
`complish.
`in a desirable form and administering the medication has
`Some investigators have suggested that it may be
`been elusive. It has not been possible to develop an
`possible to administer medication through the buccal
`acceptable candy product for use with most drugs with
`mucosa of the cheek pouch or by sublingual administra
`out heating the product to the point where degradation
`tion. See, U.S. Pat. No. 4,671,953 entitled “METHODS
`will be expected.
`45
`AND COMPOSITIONS FOR NONINVASIVE AD
`It should also be noted that pH conditions within the
`MINISTRATION OF SEDATIVES, ANALGE
`mouth may tend to adversely affect the administration
`SICS, AND ANESTHETICS.” Such administration
`of certain lipophilic drugs by the mucosal administra
`through the mucosal tissues of the mouth, pharynx, and
`tion route. It has been found in the art that administra
`esophagus of therapeutic drugs possesses a distinct use
`tion of drugs through the mucosal tissues generally
`fulness. Administration of drugs by this route does not
`occurs best when the drug is in the unionized form.
`expose the drug to the gastric and intestinal digestive
`Variations in pH affect the percentage of the drug
`juices. In addition, the drugs largely bypass the liver on
`which is unionized at a particular point in time. As a
`the ?rst pass through the body, thereby avoiding addi
`result, the pH conditions within the mouth can limit the
`tional metabolism and/or inactivation of the drug.
`effectiveness of certain drugs administered buccally or
`Generally the drugs which are administered by any
`sublingually in that those conditions cause the drug to
`of the methods described above have an unpleasant
`exist in the ionized form which is largely unavailable for
`taste. As a result, in order to allow for buccal or sublin
`transfer across the mucosal tissues.
`gual administration through the oral mucosal tissues, it
`Other potent drugs are substantially nonlipophilic
`is also necessary to incorporate the drug into some type
`and do not naturally permeate mucosal tissues. Hence it
`of pleasant tasting mass, such as a “candy" matrix.
`would be a signi?cant advancement in the artof admin
`In the manufacture of medicated candy products by
`istering potent, fast-acting drugs, if suitable methods
`existing methods, the therapeutic agent is added to a
`and compositions permitted both lipophilic and non
`lipophilic drugs to be administered transmucosally.
`molten candy mass. The resultant mixture is then thor
`oughly mixed to ensure proper distribution of the drug
`It would be another important advancement in the art
`of administering potent, fast-acting drugs, if suitable
`within the molten candy mass. The mixture is then
`methods and compositions provided a precise dosage to
`poured into a mold cavity while still molten and al
`lowed to solidify into a solid mass. Altematively, the
`a precise effect in every patient. A related advancement
`
`50
`
`55
`
`65
`
`TEVA EXHIBIT 1022
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
`15
`
`25
`
`35
`
`40
`
`5,288,497
`5
`6
`bined in order for the mixture to form an integral solid
`in the art would be to provide such methods and com
`positions that avoid the disadvantages of overdosing,
`mass. These components may include, for example,
`compressible confectioner’s sugar, sorbitol, mannitol,
`underdosing, and the immediate metabolism encoun
`and maltodextrin.
`tered in the “?rst pass effect”, yet do not involve injec
`tion by needle into the patient.
`In other embodiments within the scope of the present
`It would be a further signi?cant advancement in the
`invention, certain fats, waxes, or hydrocarbons may be
`art to provide methods and compositions for incorpo
`combined with the desired therapeutic agent and com
`rating drugs (including insoluble drugs) into a soluble
`pressed to form a dissolvable drug delivery system.
`Sugars and other carbohydrates, flavors, dyes, mold
`matrix without heating the mixture to the point that
`releasing agents, binding agents, and flavor modi?ers
`degradation occurs. It would be a related advancement
`may also be combined with the dissolvable matrix mate
`in the art to provide such a method which provided the
`capability of uniformly incorporating insoluble drugs
`rial and therapeutic agent before being compressed.
`In yet other embodiments within the scope of the
`into the soluble matrix.
`present invention, therapeutic agents may be combined
`Such compositions and methods of manufacture are
`with hydrogels or gelatins to form a dissolvable drug
`disclosed and claimed herein.
`delivery system.
`These embodiments overcome many of the problems
`of the prior art. According to the present invention,
`insoluble drugs can be added to the matrix without the
`necessity of attempting to dissolve the drug. In addition,
`the high temperatures, which are generally required to
`form a molten candy matrix of the prior art and which
`can cause degradation of some drugs, are avoided using
`the present invention. Therefore, even drugs with rela
`tively low melting points or those drugs which can
`experience decomposition below their melting points,
`can be incorporated into a dissolvable dosage-form.
`A further advantage of the present invention is that
`flavoring problems are overcome in many cases. Flexi
`bility in adding flavors is provided in that solubility of
`the components is not required in order to incorporate
`any particular ?avor into the matrix. Thus, ?avorings,
`drugs, and other components (which may be insoluble
`in liquid form) are easily mixed when they exist as a dry
`powder.
`Buffering agents and other types of pH control can
`also be added simultaneously in order to provide for
`maximum drug ef?ciency. It will be appreciated that
`drugs in the unionized form are more readily trans
`ported across the mucosal membrane. Therefore, if pH
`conditions can be adjusted to maximize the percentage
`of unionized drug available, the effectiveness of the
`drug is maximized.
`Buffering agents are particularly important for those
`drugs that partially ionize within the pH range of the
`mouth, such as weak acid and weak base drugs. Gener
`ally, buffering agents are more important when hydro
`philic drugs are used because those drugs usually have
`lower mucosal permeability and dissolve more readily
`in saliva within the mouth.
`Permeation enhancers may also be incorporated
`within the dissolvable matrix to improve the permeabil
`ity of the mucosal membrane. The permeability of both
`lipophilic and nonlipophilic drugs may be improved by
`using suitable permeation enhancers.
`Various dosage-form con?gurations are also possible
`employing the present invention. For example, layers of
`drug may be interspersed between layers of a dissolv
`able composition. Since the present invention teaches
`the use of different dissolvable matrix materials which
`can be compressed, poured, dried, or otherwise formed
`into a solid dosage-form, virtually any desired type of
`mold can be used for the formation of the dosage-form.
`It may also be desirable to incorporate a handle or
`holder in the dissolvable matrix material as the matrix is
`being formed. Alternatively, the handle may be glued to
`the matrix material by a dissolvable bonding agent, such
`as confectioner’s glue, once the dissolvable matrix is
`
`BRIEF SUMMARY AND OBJECTS OF THE
`INVENTION
`The present invention relates to compositions and
`methods of manufacture for producing medicament
`20
`compositions for use in administering potent, fast-acting
`drugs transmucosally. Furthermore, the present inven
`tion relates to such compositions and methods which
`are useful in administering drugs in a dose-to-effect
`manner such that sufficient drug is administered to pro
`duce precisely the desired effect. The invention also
`relates to a manufacturing technique that enables both
`lipophilic and nonlipophilic therapeutic agents to be
`incorporated into a ?avored dissolvable matrix material
`and to attach the matrix mixture onto an appliance or
`holder. In use, the present invention provides for the
`administration of drugs through the mucosal tissue of
`the mouth, pharynx, and esophagus, thereby avoiding
`the problems of both injection and oral administration.
`Employing the present invention, the drug may be
`introduced into the patient’s bloodstream almost as fast
`as through injection, and much faster than using the oral
`administration route, while avoiding the negative as
`pects of both methods. A dosage-form within the scope
`of the present invention can be used to administer drugs
`in a dose-to-effect manner, or until the precise desired
`effect is achieved.
`The present invention achieves these advantages by
`incorporating the drug into a dissolvable matrix mate
`rial. The dissolvable matrix may include carbohydrates,
`fats, proteins, waxes (natural and synthetic), hydrocar
`bons, and other materials which safely dissolve in the
`mouth. The dissolvable matrix, or dosage-form, can be
`used to administer drugs in a dose-to-effect manner, or