PCI‘
`
`International Bureau
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`
`
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(51) International Patent Classification 5 =
`
`A61L 9/04, A61K 9/46
`
`(11) International Publication Number:
`(43) International Publication Date:
`
`W0 91/04757
`
` A1
`
`18 April 1991 (18.04.91)
`PCT/ US90/05206
`
` (74) Agents: LITTENBERG, Joseph, S. et al.; Lerner David
`
`(21) International Application Number:
`Littenberg Krumholz & Mentlik, 600 South Avenue
`West, Westfield, NJ 07090 (US).
`13 September 1990 (13.09.90)
`
`(22) International Filing Date:
`
`
`(30) Priority data:
`
`2 October 1989 (02.10.89)
`416,152
`11 April 1990 (11.04.90)
`507,642
`
`
`
`US
`
`
`
`
` Published
`
`
`
`
`
`US
`
`[US/US]; 7325 Aspen
`INC.
`(71)Applicant: CIMA LABS,
`Lane, Minneapolis, MN 55428 (US).
`
`(72) Inventors: WEHLING, Fred ; 3033 Gettysburg Avenue N.,
`New Hope, MN 55427 (US). SCHUEHLE, Steve ; 123
`Monizoe Street, SE, Minneapolis, MN 55413 (US).
`MADAMALA, Navayanarao ; 302704 Jonquil Lane,
`Plymouth, MN 55442 (US).
`
`(81) Designated States: AT (European patent), AU, BE (Euro-
`pean patent), CH (European patent), DE (European pa—
`tent)*, DK (European patent), ES (European patent),
`FI, FR (European patent), GB (European patent), HU,
`IT (European patent), JP, KR, LU (European patent),
`NL (European patent), NO, SE (European patent), SU.
`
`With international search report.
`Before the expiration of the time limit for amending the
`claims and to be republished in the event of the receipt of
`amendments.
`
`
`
`(54) Title: EFFERVESCENT DOSAGE FORM AND METHOD OF ADMINISTERING SAME
`
`(57) Abstract
`
`The present inevntion relates to effervescent dosage forms and methods of their use. Formulations in accordance with the
`present invention are particularly useful for providing medicine to those who cannot or will not swallow a tablet.
`
`* See back of page
`
`H
`
`L
`
`I»
`
`

`

`‘l
`
`DESIGNATIONS OF “DE”
`
`Until further notice, any designation of “DE” in any international application
`whose international
`filing date is prior to October 3, 1990, shall have effect
`in the
`territory of the Federal Republic of Germany with the exception of the territory of the
`former German Democratic Republic.
`
`FOR THE PURPOSES OF INFORDIATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international
`applications under the PCT.
`‘
`
`United States of America “3
`
`Austria
`AT
`Australia
`AU
`Barbados
`BB
`Belgium
`BE
`Burkina Fasso
`BF
`Bulgaria
`BG
`Benin
`BJ
`Brazil
`BR
`Canada
`CA
`Central African Republic
`CF
`Congo
`_
`CG
`Switzerland
`CH
`CM Cameroon
`DE
`Germany
`DK
`Denmark
`
`'
`
`ES
`Fl
`FR
`GA
`GB
`GR
`HU
`IT
`JP
`KP
`
`KR
`Ll
`LK
`LU
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Greece
`Hungary
`Italy
`Japan
`Democratic People‘s Republic
`of Korea
`Republic of Korea
`Liechtenstein
`Sri lanka
`Luxembourg
`
`>
`
`MC Monaco
`MG Madagascar
`ML Mali
`MR Mauritania
`MW Malawi
`NL
`Netherlands
`N0
`Norway
`PL
`Poland
`R0
`Romania
`SD
`Sudan
`SE
`Sweden
`SN
`Senegal
`SU
`Soviet Union
`TD
`Chad
`TG
`Togo
`US
`
`fii’
`
`

`

`W0 9 1 /04757
`
`PCT/US90/05206
`
`_l_
`
`EFFERVESCENT DOSAGE FORM AND
`THOD OF ADMINISTERING SAME
`ME_________________________
`
`Technical Field
`
`invention relates to the field of
`The present
`orally ingested solid dosage
`forms.
`The present
`invention also relates to the field of oral effervescent
`dosage
`forms
`for
`the administration of
`an
`intended
`
`ingredient to children.
`
`10
`
`Background Art
`One challenge in pharmacy is that many people
`
`15
`
`20
`
`are unwilling and/or unable to swallow tablets, capsules
`or other traditional solid dosage forms.
`In particular,
`children generally do not
`like to take medicine,
`vitamins, minerals
`or dietary supplements.
`Most
`children dislike medicine because of its flavor.
`This
`problem becomes particularly acute when the medicine,
`vitamin, mineral or dietary supplement must be taken on
`
`a daily basis.
`In an attempt
`
`to make medicine, vitamins,
`
`like, more
`the
`and
`dietary supplements,
`minerals,
`palatable to children, a number of techniques have been
`employed. Many pediatric medicines are formulated with
`large amounts of sweeteners and flavorants to mask the
`taste of
`the active ingredients.
`For example,
`common
`
`25
`
`children's multivitamin pills include sweeteners
`
`and
`
`3O
`
`35
`
`and. minerals. U.s.
`flavorants together with vitamins
`Patent No.
`2,887,437 relates to a palatable vitamin
`tablet containing an amino acid. The tablet is designed
`to be
`swallowed whole,
`chewed without objectionable
`
`taste, dissolved in the mouth, or dissolved in liquids.
`It contains a plurality of vitamins,
`a nutritiona11y*
`
`essential
`
`amino
`
`acid,
`
`a
`
`flavoring
`
`agent,
`
`and
`
`a
`
`Flavored
`hydrophilic starch as a disintegration agent.
`generally
`disintegrable pills
`have,
`however,
`‘been
`ineffective
`in overcoming
`children’s
`reluctance
`to
`
`vitamins which
`particularly
`and
`taking medicines
`generally require daily administration.
`‘While
`these
`pills are less objectionable than other dosage forms,
`
`

`

`W0 9 1 /04757
`
`PCT/ US90/05206
`
`—2..
`
`the flavor
`medicine .
`
`is often overpowered by the taste of
`
`the
`
`One
`approach
`to
`the
`administration
`of
`medicines, vitamins, minerals, and the like to persons
`
`at
`
`in general is the use of effervescent tablets.
`
`Effervescence can be defined as the evolutiOn
`
`of bubbles of gas
`
`in a
`
`liquid.
`
`As set
`
`forth in
`
`chapter 6
`
`of WW
`
`Volume I, 2nd Edition, A. Lieberman, ed. 1989, Marcel
`
`Dekker,
`
`Inc.
`
`(the
`
`entirety
`
`of which
`
`is
`
`hereby
`
`incorporated by reference), effervescent mixtures have
`
`been known and used medicinally for many years.
`
`discussed in this text,
`
`and as commonly employed,
`
`As
`
`an
`
`effervescent tablet is dissolved in water to provide a
`
`carbonated or sparkling liquid drink.
`
`In such a drink
`
`the
`
`effervescence
`
`helps
`
`to mask
`
`the
`
`taste
`
`of
`
`medicaments.
`
`However,
`
`the use of effervescent tablets
`
`to prepare a beverage including medicaments,
`
`is not
`
`convenient.
`
`It
`
`requires preparatory steps before
`
`administration of
`
`the
`
`drug
`
`and
`
`also requires
`
`the
`
`presence of a suitable mixing container.
`
`In a departure from the traditional use of
`effervescence, U.S.' Patent No. 4,639,368 describes a
`
`chewing
`
`gum
`
`containing
`
`a medicament
`
`capable
`
`of
`
`absorption through the buccal cavity and a composition
`
`capable of generating carbon dioxide as a taste masking
`
`agent.
`
`The gum may optionally include a further taste
`
`bud desensitizing compound.
`
`Unfortunately there are
`
`substantial
`
`disadvantages inherent in such a gum based
`
`delivery system.
`
`Many medicants are not suited for
`
`buccal absorption.
`
`Gums are difficult
`
`to prepare.
`
`Because of braces or other dental work, many persons are
`
`not permitted to chew gum.
`
`Furthermore,
`
`the medicament
`
`must be released into solution in the saliva.
`
`Thus the
`
`full taste of the medicament is perceived, subject only
`
`to the taste masking effect.
`
`If the flavor and/or the
`
`effervescent taste masker are insufficient and/or fade
`
`prior to the full
`
`release of medicament,
`
`the patient
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`
`
`

`

`W0 9 l /04757
`
`PCT/ US90/05206
`
`-3-
`
`will be left with a gum having an objectionable taste.
`
`Gums also leave residues which must be disposed of.
`Effervescent
`tablets have also been used in
`
`the dental area. Westlake, U.S. Patent No. 1,262,888,
`Howell, U.S. Patent No. 3,962,417 and Aberg U.S. Patent
`No. 4,753,792 disclose effervescent dentifrice tablets
`adapted to foam.
`in the mouth. of a patient
`so as to
`provide a tooth cleansing action.
`Chavkin U.S. Patent No.4,613,497 discloses a
`
`water foamable pharmaceutical composition incorporating
`an effervescent agent,
`a polysaccharide gum,
`and a
`gelling' salt
`together with.
`a pharmaceutically active
`ingredient.
`The
`composition
`is
`not
`intended
`to
`immediately disintegrate but rather to form a stable
`foam in the patient’s stomach or other body cavity so
`that
`the active ingredient
`is gradually released from
`
`the foam.
`
`efforts
`towards
`Despite
`these
`and
`other
`there have been
`developments of suitable dosage forms,
`unmet needs heretofore for improved dosage forms and for
`improved methods of administration of
`systematically
`distributable pharmaceutical
`ingredients such as drugs,
`
`vitamins and the like. There also remains a need for a
`
`convenient
`and
`effective dosage
`form for
`intended
`ingredients which may be
`consumed by all children,
`including those who can’t chew a gum or swallow a pill
`
`and will be readily accepted thereby.
`
`Disclosure of the Invention
`
`invention addresses these needs.
`The present
`One aspect of
`the present
`invention provides a solid
`dosage
`form adapted for direct oral administration,
`i.e., for direct insertion into the mouth of a patient.
`A dosage form according to this aspect of the present
`invention includes a mixture incorporating at least one
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`water
`
`and/or
`
`saliva
`
`activated
`
`effervescent
`
`disintegration agent and an effective amount of at least
`one
`systematically distributable
`ingredient.
`The
`mixture is present as a 'tablet of a size and shape
`
`

`

`W0 9 1 /04757
`
`PCT/ US90/05206
`
`_4—
`
`adapted for direct oral administration to a jpatient,
`
`desirably a human patient.
`
`The tablet is substantially
`
`completely disintegrable upon exposure to water and/or
`
`saliva.
`
`The
`
`effervescent disintegration agent
`
`is
`
`present in an amount effective to aid in disintegration
`
`of the tablet,
`
`and to provide a distinct sensation of
`
`effervescence when the tablet is placed in the mouth of
`
`a patient.
`
`The
`
`effervescent
`
`sensation
`
`is
`
`not
`
`only
`
`pleasant
`
`to the patient but also tends to stimulate
`
`saliva production,
`
`thereby providing additional water to
`
`aid in further effervescent action.
`
`Thus,
`
`once the
`
`tablet
`
`is placed in the patient’s mouth,
`
`it will
`
`disintegrate
`
`rapidly
`
`and
`
`substantially
`
`completely
`
`without
`
`any voluntary action by the patient.
`
`The
`
`systemically' distributable ingredient.
`
`is thus carried
`
`into solution or into suspension in the patient’s own
`
`saliva, which the patient ordinarily swallows.
`
`Even if
`
`the patient does not
`
`cheW'
`
`the tablet, disintegration
`
`will proceed rapidly. Therefore, dosage forms according
`
`to the aspect of the present invention are particularly
`
`in administration of medications to individuals
`useful
`who
`cannot or will not
`chew,
`such as debilitated
`
`patients,
`
`patients who
`
`have difficulty swallowing
`
`solids, and the elderly.
`
`According to one particularly preferred aspect
`
`of the invention,
`
`there is provided an oral pediatric
`
`vitamin supplement comprising a mixture of at least one
`
`effervescent disintegration agent, and a pediatrically
`
`effective amount of at
`
`least one intended ingredient
`
`selected from the group consisting of vitamins
`
`and
`
`minerals
`
`and mixtures
`
`thereof.
`
`The mixture most
`
`preferably is present in the form of a compressed tablet
`
`of
`
`a
`
`size
`
`and
`
`shape
`
`adapted.
`
`for
`
`direct
`
`oral
`
`administration to children and which will rapidly and
`
`completely
`
`disintegrate
`
`when
`
`administered.
`
`The
`
`effervescent disintegration agent
`
`is present
`
`in an
`
`amount which.
`
`is effective both.
`
`to aid in the rapid
`
`10
`
`15
`
`20
`
`25
`
`3O
`
`35
`
`

`

`W0 91 /O4757
`
`PCT/ US90/05206
`
`-5—
`
`disintegration of the tablet and to provide a positive
`organoleptic sensation to children.
`According to a particularly preferred aspect
`invention ,
`the
`systemical ly
`distributable
`the
`of
`ingredient is a pharmaceutical
`ingredient
`including at
`least
`one
`psychotropic
`drug
`such
`as
`a
`sedative,
`antidepressant, neuroleptic, or hypnotic.
`The present
`invention is especially valuable with psychotropic drugs
`in that a patient receiving such drugs, particularly a
`patient in a mental institution, often attempts to hold
`a conventional
`tablet or capsule concealed within his
`mouth rather than swallow it.
`The patient may then
`surreptitiously remove
`the
`tablet or
`capsule when
`medical personnel are not present.
`The preferred dosage
`forms according to this aspect of the present invention
`are
`substantially
`resistant
`to
`such
`concealment ,
`inasmuch as they will disintegrate rapidly even if they
`
`are concealed within the mouth.
`
`Children readily accept
`the tablets of
`the
`invention, not only because the effervescent
`present
`disintegration agent provides
`for
`the controlled and
`rapid disintegration of the tablet when placed in the
`mouth or because the effervescent disintegration agent,
`by its action, aids in the masking of the potentially
`objectionable tastes of the vitamins, medicines and/or
`minerals.
`Rather,
`it
`is the positive organoleptic
`sensation achieved by the effervescent action in the
`
`of
`sensation
`and
`speed
`texture ,
`the
`mouth ,
`and the size and shape of
`the tablet
`disintegration,
`which is adapted for children which,
`in combination,
`result
`in breaking down children's
`apprehension to
`taking the tablet.
`The combined sensations achieved by
`the preferred dosage forms according to this aspect of
`the present
`invention are accepted by children to a
`surprising degree.
`It has been found i’that children
`enjoy both the taste and the tactile sensation of
`sucking on or chewing an effervescent delivery system of
`the
`type described and
`claimed herein.
`This
`is
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`

`

`W0 91/04757
`
`PCI'/ US90/05206
`
`—6—
`
`particularly important when, as in the case of vitamins,
`
`a child must take a particular intended ingredient on a
`
`daily basis.
`
`Furthermore,
`
`because
`
`the
`
`positive
`
`1‘)
`
`organoleptic sensation may be realized by either chewing
`
`or by sucking' on a tablet according to the present
`
`invention, the widest range of children may benefit.
`
`In preferred
`
`embodiments
`
`of
`
`the
`
`present
`
`invention,
`
`the effervescent disintegration agent may
`
`include, without limitation, at least one acid selected
`
`from the group consisting of citric acid, tartaric acid,
`
`malic acid,
`
`fumaric acid, adipic acid,
`
`succinic acid,
`
`acid anhydrides and acid salts and mixtures thereof, and
`
`at least one base selected from the group consisting of
`
`carbonate salts, bicarbonate salts and mixtures thereof.
`
`In addition to masking
`
`the objectionable
`
`flavor of medicants,
`
`the effervescence of the tablets of
`
`the present
`
`invention facilitate the disintegration
`
`thereof.
`
`Furthermore,
`
`the use of
`
`the effervescent
`
`disintegration agent of the present invention provides a
`
`pleasant oral organoleptic sensation. Organoleptic is
`
`understood to mean being, affecting, or relating to the
`
`that
`qualities of the tablets of the present invention,
`stimulate the sensory organs.
`These may include taste,
`
`odor,
`
`and/or
`
`feel of
`
`the
`
`tablets
`
`of
`
`the present
`
`invention while in the mouth of
`
`the child to whom
`
`administered.
`
`According to a further aspect of the present
`
`invention, the systemically distributable pharmaceutical
`
`ingredient
`
`is preferably a pharmaceutical
`
`ingredient
`
`which may be provided in microencapsulated form.
`
`Thus,
`
`the mixture may include microcapsules each incorporating
`
`a systemically distributable pharmaceutical
`
`ingredient
`
`and
`
`an
`
`encapsulant
`
`surrounding
`
`the
`
`pharmaceutical
`
`ingredient.
`
`Upon disintegration of such a tablet,
`
`the
`
`individual microcapsules are released and dispersed in
`
`the patient’s mouth in. admixture ‘with the patient’s
`
`saliva whereupon the microcapsules are conducted to the
`
`digestive tract for systemic distribution.
`
`10
`
`15
`
`20
`
`25
`
`3O
`
`35
`
`

`

`W0 91/04757
`
`PCT/ US90/05206
`
`_7_
`
`The
`
`combination
`
`of
`
`the
`
`effervescent
`
`disintegration agent and the ndcrocapsules provides a
`uniquely
`effective
`dosage
`form for
`systemically
`distributable pharmaceutical
`ingredients which
`have
`unpleasant
`flavors or which should not be
`released
`within the mouth for other reasons. Because the tablet
`will disintegrate without
`chewing,
`the
`problem 'of
`microcapsule rupture during chewing of
`the tablet
`is
`substantially eliminated.
`Stated another way,
`the
`effervescent action allows administration of the tablet
`
`without chewing,
`
`so as to maintain the efficacy of the
`
`microencapsulant.
`The present invention also encompasses methods
`of administering ingredients to a patient.
`In a method
`
`a
`invention,
`the present
`according to this aspect of
`dosage form,
`such as the dosage forms described above,
`is provided to a patient and administered by placing the
`solid dosage
`form in the patient's mouth.
`Most
`preferably,
`the dosage form is substantially completely
`disintegrated in the patient's mouth by contact with the
`saliva.
`The effervescent disintegration ingredient
`
`provides a distinct effervescent sensation in the mouth,
`which stimulates salivation and thus further promotes
`
`the
`Most desirably,
`the disintegration process.
`conducted
`substantially
`disintegration
`process
`is
`without chewing or crushing of the tablet in the mouth.
`
`In methods according to this aspect of
`
`the
`
`the patient may be a person unwilling
`present invention,
`or unable to chew such as a recalcitrant or disabled
`
`patient, or an elderly patient.
`is
`Also
`provided
`hereby
`administering
`a
`microencapsulated
`distributable pharmaceutical
`ingredient
`
`of
`a method
`systemically
`to a patient.
`
`This is accomplished by placing a tablet as discussed
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`above which includes at
`
`least one microencapsulated
`
`pharmaceutical
`systemically distributable
`into the mouth of
`a patient whereupon
`
`ingredient
`the tablet
`
`completely dissolves without
`
`chewing or crushing by
`
`

`

`W0 9 l /04757
`
`PCT/ US90/05206
`
`—8—
`
`mastication.
`
`The intact microcapsules released into the
`
`saliva thereby are conducted to the digestive tract for
`
`systemic distribution of the pharmaceutical
`
`ingredient
`
`w
`
`encapsulated therein.
`
`In a preferred aspect of the present invention
`
`particularly useful when administering a dosage form to
`
`a patient who seeks to defeat the administration by not
`
`swallowing the tablet,
`
`the administration is accompanied
`
`by observing the patient for a period of time sufficient
`
`for
`
`said tablet
`
`to completely disintegrate.
`
`By
`
`observation,
`
`the patient can be prevented from expelling
`
`the dosage form for sufficient
`
`time such that it may
`
`disintegrate.
`
`Best Mode For Carrying Out the Invention
`
`An
`
`oral
`
`dosage
`
`form according
`
`to
`
`one
`
`embodiment of
`
`the present
`
`invention is a tablet of a
`
`size and shape adapted for direct oral administration,
`
`and preferably oral administration to children. As used
`
`in this disclosure,
`
`the term ”child” refers to a person
`
`under the age of about 16 years.
`
`The pediatric dosage
`
`forms according to this aspect of
`
`the invention are
`
`preferably useful for children under the age of about 12
`years.
`For children under the age of 12 years,
`tablets
`having a volume less than about 2.0 cm3, and desirably
`less than about 1.0 cm3 are preferred.
`The mass of each
`
`such tablet generally should be less than about 3.0 g
`
`and more preferably less than about 1.5 g.
`
`The tablet
`
`may include surface markings, cuttings, grooves, letters
`
`and or numerals
`
`for the purpose of decoration and/or
`
`identification.
`
`The
`
`tablet
`
`is, of course,
`
`in solid
`
`form.
`
`Preferably,
`
`the tablet
`
`is a hard compressed
`
`tablet.
`
`It
`
`includes
`
`one
`
`or more
`
`systemically
`
`distributable ingredients, together with an effervescent
`
`disintegrating agent.
`
`The size of the tablet is also
`
`dependent upon the amount of material used, however, it
`
`is preferable to provide tablets which have a largest
`
`dimension of about 11/16 inches.
`
`10
`
`15
`
`20
`
`25
`
`3O
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`35
`
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`-9—
`
`When used for children,
`
`the tablet may have
`
`the shape of letters, numbers, animals, birds, cartoon
`characters, fish, dinosaurs, and the like. Further,
`the
`tablet may include surface markings, cuttings, grooves,
`letters and or numerals for the purpose of decoration
`and/or
`identification.
`The ‘tablet.
`is,
`of‘ course,
`in
`solid form. Preferably,
`the tablet is a hard compressed
`
`tablet.
`
`It includes one or more intended ingredients,
`
`together with an effervescent disintegrating agent.
`The
`term
`”systemically
`distributable
`
`should be
`in this disclosure
`used
`as
`ingredient”
`understood to mean an ingredient(s),
`the injestion of
`
`which is the reason for consuming a tablet in which the
`
`ingredient is included. These ingredients are conducted
`from the mouth to the digestive system for absorption
`
`stomach
`the
`through
`distribution through
`
`or
`the
`
`intestines
`bloodstream.
`
`and
`
`systemic
`The
`term
`
`ingredient”
`”pharmaceutical
`intended to be
`is not
`limited
`to
`pharmaceutical
`ingredients which
`are
`systemically active or which systemically distribute
`over time.
`For the purposes of the present invention, a
`
`include
`may
`ingredient
`distributable
`systemically
`dietary
`and
`vitamins
`pharmaceuticals
`or. minerals,
`supplements. Mixtures of any of the foregoing are also
`contemplated by
`the term systemically distributable
`
`pharmaceutical ingredient.
`By the term pharmaceutical(s) applicants mean
`
`include, without
`may
`Pharmaceutica1(s)
`drug.
`a
`limitation, antacids, analgesics, anti-inflammatories,
`
`10
`
`15
`
`20
`
`25
`
`3O
`
`antibiotics,
`
`laxatives,
`
`anorexics,
`
`antiasthmatics,
`
`antidiuretics,
`
`antiflatuents,
`
`antimigraine
`
`agents,
`
`antispasmodics,
`
`sedatives,
`
`antihyperactives,
`
`tranquilizers,
`
`antihistamines,
`
`decongestants,
`
`beta—
`
`blockers, and combinations thereof.
`
`35
`
`As used in this disclosure,
`
`the term vitamin
`
`refers to trace organic substances that are required in
`
`the diet.
`
`For
`
`the purposes of the present
`
`invention,
`
`the
`
`term.
`
`vitamin(s)
`
`include, without
`
`limitation,
`
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`thiamin,
`
`riboflavin, nicotinic acid, pantothenic acid,
`
`pyrdoxine, biotin, folic acid, vitamin B12,
`
`lipoic acid,
`
`ascorbic acid, vitamin A, vitamin D, vitamin E
`
`and
`
`vitamin K. Also included within the term vitamin are
`
`the coenzymes thereof.
`
`Coenzymes are specific chemical
`
`“I
`
`forms
`
`of
`
`vitamins.
`
`Coenzymes
`
`include
`
`thiamine
`
`pyrophosphates
`
`(TPP),
`
`flavin mononucleotide
`
`(FMM),
`
`flavin adenine dinucleotive (FAD), Nicotinamide adenine
`
`dinucleotide (NAD), Nicotinamide adenine dinucleotide
`
`10
`
`phosphate (NADP) Coenzyme A (CoA) pyridoxal phosphate,
`
`biocytin,
`
`tetrahydrofolic
`
`acid,
`
`coenzyme
`
`lipoyllysine,
`
`ll—cis-retinal,
`
`and
`
`1,25—
`
`dihydroxycholecalciferol.
`
`The
`
`term vitamin(s)
`
`also
`
`includes choline, carnitine, and alpha, beta, and gamma
`
`15
`
`carotenes.
`
`As used in this disclosure,
`
`the term ”mineral”
`
`refers to inorganic substances, metals,
`
`and the like
`
`required in the human diet. Thus, the term ”mineral” as
`
`used herein includes, without limitation, calcium,
`
`iron,
`
`20
`
`selenium, copper,
`
`iodine, magnesium, phosphorus,
`
`zinc,
`
`chromium and the like, and mixtures thereof.
`
`The term ”dietary supplement” as used herein
`means a substance which has an appreciable nutritional
`
`effect when administered in small
`
`amounts.
`
`Dietary
`
`supplements
`
`include,
`
`without
`
`limitation,
`
`such
`
`ingredients as bee pollen, bran, wheat germ, kelp, cod
`
`liver oil, ginseng, and fish oils, amino-acids, proteins
`
`and mixtures thereof.
`
`As will be appreciated, dietary
`
`supplements may incorporate vitamins and minerals.
`
`The
`
`amount
`
`of
`
`systemically distributable
`
`ingredient
`
`incorporated in each tablet may be selected
`
`according to known principles of pharmacy. An effective
`
`amount
`
`of
`
`systemically distributable
`
`ingredient
`
`is
`
`specifically contemplated.
`
`By
`
`the
`
`term effective
`
`amount,
`
`it
`
`is understood that, with respect
`
`to for
`
`example pharmaceuticals,
`
`a pharmaceutically' effective
`
`amount
`
`is contemplated.
`
`A. pharmaceutically‘ effective
`
`amount
`
`is
`
`the
`
`amount or quantity of
`
`a
`
`drug or
`
`25
`
`30
`
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`
`pharmaceutically active substance which is sufficient to
`elicit the required or desired therapeutic response, or
`in other words,
`the amount which is sufficient to elicit
`an appreciable biological response when administered to
`a patient.
`.A pediatrically effective amount, as used
`herein,
`refers
`to
`the
`amount
`of
`a
`vitamin,
`pharmaceutical, mineral and/or dietary supplement which
`is
`sufficient
`to elicit
`an
`appreciable biological
`response when administered to a child.
`As used with
`reference to a vitamin or mineral,
`the terms ”effective
`
`and ”pediatrically effective amount” mean an
`amount”
`at
`least
`about
`10% of
`the United States
`amount
`Recommended Daily Allowance (”RDA”) of that particular
`ingredient for a patient, or for a child in the latter
`case.
`For
`example,
`if
`an
`intended ingredient
`is
`vitamin C,
`then an effective amount or a pediatrically
`effective amount of vitamin C would include an amount of
`
`vitamin C sufficient to provide 10% or more of the RDA.
`Typically, where
`the tablet
`includes
`a mineral or
`vitamin, it will incorporate higher amounts, preferably
`
`about 100% or more of the applicable RDA.
`
`The term effervescent disintegration agent(s)
`compounds' which evolve gas;
`The preferred
`includes
`effervescent agents evolve gas
`by' means of chemical
`reactions which
`take place
`upon
`exposure
`of
`the
`
`effervescent disintegration agent
`
`to water and/or
`
`to
`
`saliva in the mouth.
`
`10
`
`15
`
`20
`
`25
`
`The bubble or gas generating reaction is most
`
`often the result of
`
`the reaction of a soluble acid
`
`30
`
`source
`
`and
`
`an alkali metal
`
`carbonate or
`
`carbonate
`
`source.
`The reaction of these two general classes of
`compounds produces carbon dioxide gas upon contact with
`water included in saliva.
`1
`Such water activated materials must be kept in
`
`35
`
`a generally anhydrous state with little or no absorbed
`moisture or in a stable hydrated form since exposure to
`
`water' will prematurely' disintegrate 'the ‘tablet.
`
`The
`
`acid sources or acid may be any which are safe for human
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`consumption and may generally include food acids, acid
`
`anhydrides and acid salts.
`
`Food acids include citric
`
`acid,
`
`tartaric acid, malic acid,
`
`fumaric acid, adipic
`
`acid, and succinic acids etc.
`
`Because these acids are
`
`directly ingested,
`
`their overall solubility in water is
`
`less important
`
`than it would be if the effervescent
`
`tablet
`
`formulations
`
`of
`
`the present
`
`invention were
`
`intended to be dissolved in a glass of water.
`
`Acid
`
`anhydrides and acid of
`
`the above described acids may
`
`also be used. Acid salts may include sodium, dihydrogen
`
`pyrophosphate,
`disodium dihydrogen
`phosphate,
`citrate salts and sodium acid sulfite.
`
`acid
`
`Carbonate sources include dry solid carbonate
`
`and bicarbonate salts such as sodium bicarbonate, sodium
`
`carbonate ,
`
`potassium bicarbonate
`
`and
`
`potassium
`
`carbonate,
`
`magnesium
`
`carbonate
`
`and
`
`sodium
`
`sesquicarbonate,
`
`sodium glycine
`
`carbonate, L-lysine
`
`carbonate,
`carbonate.
`
`arginine carbonate
`
`and
`
`amorphous
`
`calcium
`
`The effervescent disintegration agent(s)
`
`of
`
`the present
`
`invention is not
`
`always based upon
`
`a
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`reaction which forms carbon dioxideh Reactants which
`evolve oxygen or other gasses which are pediatrically
`
`safe are also considered within the scope. Where the
`
`effervescent
`
`agent
`
`includes
`
`two mutually
`
`reactive
`
`components,
`
`such as
`
`an acid source and a carbonate
`
`source,
`
`it
`
`is preferred that both components
`
`react
`
`completely.
`
`Therefore,
`
`an
`
`equivalent
`
`ratio
`
`components which provides
`
`for
`
`equal
`
`equivalents
`
`of
`
`is
`
`preferred.
`
`For example,
`
`if the acid used is diprotic,
`
`then
`
`either
`
`twice
`
`the
`
`amount
`
`of
`
`a mono-reactive
`
`carbonate base, or an equal amount of a di-reactive base
`
`should be
`
`used
`
`for
`
`complete neutralization to be
`
`realized. However,
`
`in other embodiments of the present
`
`invention,
`
`the amount of either acid or carbonate source
`
`may exceed the amount of the other component. This may
`
`be useful
`
`to enhance taste and/or performance of
`
`a
`
`tablet containing an overage of either component.
`
`In
`
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`

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`this case, it is acceptable that the additional amount
`
`of either component may remain unreacted.
`In
`general,
`the
`amount
`of
`effervescent
`disintegration agent of the present invention useful for
`the
`formation of
`tablets
`according to the present
`
`invention should range from about.
`
`5
`
`to about
`
`50% ‘by
`
`weight of the final composition, and preferably between
`about 15 and about
`3096 by weight
`thereof.
`In a more
`
`effervescent
`of
`amount
`the
`embodiment,
`preferred
`disintegration agent according to the present
`invention
`ranges from between about 20 and about 25% by weight of
`
`the total composition.
`
`More specifically,
`
`tablets according to the
`
`of
`amount
`an
`contain
`should
`invention
`present
`effervescent. disintegration. agent. effective ‘to aid in
`
`tablet
`the
`the rapid and complete disintegration of
`when orally administered.
`By "rapid",
`it_is understood
`
`that
`
`the
`
`tablets of
`
`the present
`
`invention should
`
`disintegrate in the mouth of a patient in less than 10
`minutes,
`and desirably between about
`30
`seconds
`and
`about 7 minutes.
`In a particularly preferred embodiment
`
`the tablet should
`invention,
`according to the present
`dissolve in the mouth in between about 30 seconds and
`
`about 5 minutes. Disintegration time in the mouth can
`
`10
`
`15
`
`20
`
`25
`
`be measured by observing the disintegration time of the
`
`tablet in water at about 37°C.
`
`The tablet is immersed
`
`in
`
`the water without
`
`forcible
`
`agitation.
`
`The
`
`disintegration time
`
`is the time
`
`from immersion for
`
`substantially complete dispersion of
`
`the tablet
`
`as
`
`30
`
`determined by visual observation.
`
`As further discussed
`
`below,
`
`tablets according to the invention, may include
`
`microcapsules or other discrete inclusions.
`
`These may
`
`be insoluble or' more
`
`slowly soluble than 'the tablet
`
`binder.
`
`As used in this disclosure the term ”complete
`
`35
`
`require
`not
`does
`tablet
`the
`of
`disintegration”
`dissolution or disintegration of such microcapsules or
`
`other
`
`discrete
`
`inclusions.
`
`Disintegration
`
`times
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`referred to in this disclosure should be understood as
`
`determined by this method unless otherwise specified.
`
`Also,
`
`the
`
`amount
`
`of
`
`effervescent
`
`a!
`
`disintegration agent. present
`
`in the tablet
`
`should. be
`
`effective to provide an effervescent sensation in the
`
`mouth of the patient who consumes the tablet. Thus,
`
`the
`
`patient should be able to perceive a distinct sensation
`
`of "fizzing" or bubbling as the tablet disintegrates in
`
`the mouth.
`
`To provide this sensation,
`
`the amount of
`
`effervescent agent
`to provide about
`
`in each tablet desirably is arranged
`20
`to about
`60
`cm3 of gas.
`The
`
`”fizzing"
`
`sensation
`
`substantially
`
`enhances
`
`the
`
`organoleptic effects of the tablet. Thus,
`
`the amount of
`
`effervescent disintegration agent useful
`
`in accordance
`
`with the present
`
`invention is also an amount effective
`
`to provide
`
`a positive organoleptic
`
`sensation to a
`
`patient.
`
`A. ”positive” organoleptic, sensation.
`
`is one
`
`which
`
`is pleasant or
`
`enjoyable
`
`and which
`
`can
`
`be
`
`perceived readily by a normal human being..
`
`It should also be noted that the hardness of a
`
`tablet may also play a
`
`role in disintegration,
`
`time.
`
`increasing the hardness of a tablet may
`Specifically,
`increase the disintegration.
`time
`just
`as decreasing
`
`10
`
`15
`
`20
`
`25
`
`hardness may decrease disintegration time.
`The dosage form according to this aspect of
`
`the present
`
`invention may further include one or more
`
`additional adjuvants which can be chosen from those
`
`known in the art including flavors, dilutents, colors,
`
`binders,
`
`filler,
`
`compaction
`
`vehicles,
`
`and
`
`non—
`
`effervescent disintegrants.
`
`Examples of binders which can be used include
`
`acacia,
`
`tragacanth, gelatin, starch, cellulose materials
`
`such as methyl cellulose and sodium carboxy methyl
`
`cellulose, alginic acids and salts thereof, magnesium
`
`aluminum silicate,
`
`polyethylene
`
`glycol,
`
`guar
`
`gum,
`
`polysaccharide acids, bentonites, sugars,
`
`invert sugars
`
`and the like. Binders may be used in an amount of up
`
`30
`
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`to 60 weight percent and preferably about 10 to about 40
`
`weight percent of the total composition.
`Non—effervescent
`disintegrants
`
`include
`
`starches as corn starch, potato starch and modified
`
`starches thereof, sweeteners, clays, such as bentonite,
`
`micro-crystalline cellulose,
`alginates,
`gums
`such as
`agar, guar,
`locust bean, karaya, pecitin and tragacanth.
`Disintegrants may comprise up to about 20 weight percent
`and preferably between about 2 and about 10 percent of
`
`10
`
`the total weight of the composition.
`
`Coloring agents may include titanium dioxide,
`
`and dyes
`
`suitable for
`
`food such as
`
`those known as
`
`F.D.& C. dyes and natural coloring agents such as grape
`
`skin extract, beet
`
`red powder, beta—carotene, annato,
`
`15
`
`carmine,
`
`turmeric,
`
`paprika,
`
`etc..
`
`The .amount
`
`of
`
`coloring used may range from about 0.1 to about 3.5
`
`20
`
`25
`
`weight percent of the total composition.
`
`Flavors,
`
`incorporated in the composition may
`
`be
`
`chosen from synthetic flavor oils and
`
`flavoring
`
`aromatics and/or natural oils, extracts from plants,
`leaves,
`flowers,
`fruits and so forth and combinations.
`thereof.
`These may
`include
`cinnamon oil, oil of
`
`Wintergreen, peppermint oils, clove oil, bay oil, anise
`
`oil, eucalyptus,
`thyme oil,
`cedar
`leave oil, oil of
`nutmeg, oil of sage, oil of bitter almonds and cassia
`oil.
`Also useful as flavors are vanilla, citrus oil,
`including lemon, orange, grape,
`lime a