EXHIBIT 1004 
`
`Coalition For Affordable Drugs XI LLC
`Exhibit 1004
`Coalition For Affordable Drugs XI LLC v Insys Pharma, Inc.
`IPR2015-01797
`
`

`
`USOO5370862A
`5,370,862
`[11] Patent Number:
`[19]
`Umted States Patent
`
`Klokkers-Bethke et al.
`[45] Date of Patent:
`Dec. 6, 1994
`
`4,744,495
`5/1988 Warby ............................ 222/402.16
`1112291: 712:: 1- ------------=1 23:72:
`,
`,
`s nan e
`.
`5,047,230
`9/1991 Nagy et al.
`...............
`424/45
`5,125,466
`6/1992 Felt et a1.
`............................ 177/207
`
`
`
`FOREIGN PATENT DOCUMENTS
`Egg Pat‘ Off" ‘
`
`OTHER PUl3LICATIONS
`g\::1gcl<)0Il1t1yt1e;x, 10th ed., Wmdholz et al. (1983) p. 1095,
`Primary Examz‘ner—Thurman K. Page
`Assistant Examiner—Robert H. Harrison
`Attorney, Agent, or Firm——Marsha.ll, O’Too1e, Gerstein,
`Murray & Borun
`ABSTRACT
`[57]
`_
`_
`.
`A pharmaceutlcal aerosol spray for treaung an angma
`attack including a container having a liquid composition
`;1;,e;ei;,g°g*,P,Ij:i;1§,°~1WWeightPer°ent°fni*r°g!y°-
`g t percent of ethanol, 2 to 60 we1ght
`,
`percent ofpropylene glycol, 10 to 50 weight percent of
`dichlorodifluoromethane and 30 to 70 weight percent of
`dichlorotetrafluoroethane, the container having a valve
`ixlslsemblyaisnealegl to th:lco:1tainter
`finhopeninf in
`leccggixil
`C/1 a:faSen:1:E;
`3 3'
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`10 Claims, 1 Drawing Sheet
`
`[75]
`
`[73] Assignee:
`
`PHARMACEUTICAL HYDROPHILIC
`SPRATRYCEONWWG
`FOR
`ATING ANGINA
`Inventors: Karin Klokkers-Bethke; Ulrich
`Miinch both of Monheim/Rh1d.,
`Gemahy
`Schwarz Pharma AG, Monheim,
`Germany
`[21] App]. No’: 989,987
`[22] Filed:
`Dec. 11’ 1992
`Related U.S. Application Data
`.
`.
`.
`§:;nm::;:té°n_m-pan of Set’ N°' 709’58l’ Jun" 3’ 1991’
`'
`F
`’ A H ti
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`pp ca on nonty a
`Jun. 13, 1990 [DE] Germany ............................. 4018919
`
`[63]
`30
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`[56]
`
`Int. Cl.5 ................................................ AGIK 9/12
`[51]
`"'S;§‘/'2aa:1z;‘111725;'51‘s‘;215?£‘$Z>%§3{333713;
`‘S2’
`_
`[58] Fleld of Search ............... 424/45, 47; 128/200.13,
`128/200' 14; 215/247; 141/20; 222/394
`References (fited
`U.S_ PATENT DOCUMENTS
`SHSOII CC 3.1. ...........................
`4,349,135 9/1982 Busselet .....
`...... 222/394
`
`4,440,777 4/1984 Zupan .......
`424/45 x
`4,487,334 12/1984 Werding .......
`222/55
`4,621,964 11/1986 Radtke et al. ........................... 413/9
`
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`1
`
`5,370,862
`
`5
`
`10
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`15
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`20
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`30
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`35
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`50
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`55
`
`PHARMACEUTICAL HYDROPHILIC SPRAY
`CONTAINING NITROGLYCERIN FOR TREATING
`ANGINA
`
`This application is a continuation-in-part, of applica-
`tion Ser. No. 07/709,581, filed Jun. 3, 1991, abandoned.
`This invention pertains to a liquid nitroglycerin
`spray, desirably having a hydrophilic base, and a sealant
`material for a container having the spray composition
`therein and which sealant contacts the spray composi-
`tion, the nitroglycerin absorption value of the sealant
`being less than 10 mg of nitroglycerin per one gram of
`sealant material.
`
`BACKGROUND OF THE INVENTION
`
`Nitroglycerin, also called glycerol trinitrate or GTN,
`is an active substance for the treatment of angina pecto-
`ris attacks. Among other things, it is used in emergen-
`cies when the medication should be fast acting.
`The pharmaceutical agents used for this specific pur-
`pose, such as sublingual tablets or crunchable capsules,
`have disadvantages. A disadvantage, amongst others, is
`that after intake the active agent in these pharmaceuti-
`cal agents must first be released and dispersed prior to
`being available for resorption in dissolved form. Fur-
`thermore, the loss of time needed to take the pharma-
`ceutical agent out of a blister package can be critical
`during an acute angina attack.
`To avoid the disadvantages of the described pharma-
`ceutical forms, nitroglycerin-containing sprays have
`been developed. By spraying a dose of the active agent
`into the buccal area of the mouth, a direct and rapid
`dispersion of a solution of the active agent over as large
`a portion as possible of the oral mucosa, which absorbs
`the active agent nitroglycerin was to be achieved. In
`this way, a large area was to be reached, thereby accel-
`erating absorption of the active agent.
`The previously known nitroglycerin pharmaceutical
`solutions are characterized by high vapor pressure,
`solution properties, and an explosive nature which have
`limited their use and acceptance. Therefore, a desensi-
`tized active agent-—supplementary agent mixture has to
`be used for safety reasons during the formulation of the
`pharmaceutical agent spray.
`Based on its lipophilic characteristics, nitroglycerin is
`readily soluble in solvents such as ether, acetone, ethy-
`lacetate, benzol, chloroform and triglycerides. On the
`other hand, the solubility of nitroglycerin in hydro-
`philic solvents, such as water, is limited. The solubility
`of nitroglycerin in water amounts to merely about 1.1
`mg/ml.
`Because of the low solubility of nitroglycerin in
`water the solvents used in the customary spray formula-
`tions are lipophilic, i.e. oils or triglycerides. However,
`the lipophilic solvents prevent dispersion of the active
`agent nitroglycerin into the hydrophilic mucosa with
`the desired speed during acute angina pectoris attacks.
`Previously, if it was desired to increase the availabil-
`ity of an active agent, the amount of the lipophilic sol-
`vent was reduced. However, the nitroglycerin surge
`duration, measurable via the maximum plasma nitro-
`glycerin glycerin concentration (Cmax) and the time of
`the maximum concentration (tmax), was only insignifi-
`cantly affected.
`It is reported that P.M. Dewland et al [Heart and
`Vessels, 7, 536-544 (l987)] obtained higher Cm; values
`(Table 1) for three nitroglycerin sprays, manufactured
`
`2
`with lipophilic solutions, by decreasing the amount of
`the lipophilic formulation portions; however, the tmw; is
`not significantly different.
`Another way to increase the availability of the active
`agent is described in the DE-A 32 46 081. That refer-
`ence discloses increasing the propellant portion to
`60-95% by weight of the formulation. The increased
`propellant portion effects a higher concentration of the
`active agents in non-volatile oily solvents. Furthermore,
`the active agent must first diffuse in the mucosa from
`the oily active agent solution. However, the surge of the
`active agent, which is important when the angina attack
`occurs, cannot be significantly shortened. Also, for
`reasons of increased environmental consciousness, it is
`undesirable to increase the amount of propellant, so this
`should be avoided.
`
`A qualitatively significant improvement in treating an
`angina attack is not possible if lipophilic solvents are
`retained in the spray.
`Another starting point for quickly dispersing the
`active agent in the hydrophilic mucosa, is the use of a
`solution with dissolving characteristics which are as
`small as possible for the active agent nitroglycerin. In
`this regard, it is necessary to take into consideration that
`the spray formulation solution or solution mixture de-
`sensitizes the active agent nitroglycerin sufficiently and
`also that the solution be technically easy to handle with
`respect to production requirement.
`U.S. Pat. No. 3,155,574 describes a nitroglycerin
`spray formulation-for inhalation using a hydrophilic
`solution base containing the active agent nitroglycerin,
`1,2-propanediol and ethanol free of water, but actual
`exemplified embodiments of the primary packaging
`means are missing. However, inhalation is rather detri-
`mental to a patient during the occurrence of an angina
`attack since it is more difficult to carry out. More desir-
`able are nitroglycerin-containing sprays in which the
`active agent is sufficiently absorbed through the oral
`mucosa, so that inhalation of the active agent is not
`necessary.
`Investigations by H. Laufen et al, reported in Ther-
`apy Week, 34, 963-970 (1984) indicated that when a
`hydrophilic formulation, as compared to nitroglycerin-
`containing sprays using a lipophilic base, is used the
`amount of the active agent in the blood, as well as the
`amount of the absorbed substance, is faster and greater
`than when a lipophilic base is used. The authors report
`use of a pump spray for closing the solution. We know
`from general experience that pump sprays presently do
`not meet the requirements for administering pharma-
`ceutical agents so that the formulation or composition
`of Laufen et al having the described therapeutically
`beneficial effect cannot be converted into a useful phar-
`maceutical agent.
`The EP-A 0 310 910 describes a nitroglycerin-con-
`taining spray formulation which, besides the active
`agent, contains only ethanol and water as a solvent and
`is adjusted to a pH value of 2.4 to 6.7. However, during
`evaporation of the ethanol the active agent in this for-
`mulation experiences a phase separation from the water
`and thus is not present in a desensitized form, even
`though desensitization actually is desirable for safety
`reasons.
`
`65
`
`to
`The present state of technology with respect
`sprays having a hydrophilic base, as compared to those
`having a lipophilic base, reveals shortcomings, such as
`an absorption of nitroglycerin in the valve component
`parts and a reduction of the dosage amount of the active
`
`

`
`3
`agent nitroglycerin during each new or individual spray
`puff or shot.
`SUMMARY OF TEE INVENTION
`
`5,370,862
`
`4
`solution of 13.83 weight-% ethanol and 7.28 weight-%
`1,2-propyleneglycol and a propellant portion of 78.16
`weight-%, and with this composition being in essen-
`tially constant contact with a container sealant material,
`the absorption value of which is less than 10 mg of
`nitroglycerin per one gram of sealant material, and
`particularly is in the range of 0.1 to 9.9 mg of nitroglyc-
`erin per one gram of sealant material.
`Besides the previously mentioned main component
`parts, the nitroglycerin spray according to this inven-
`tion may contain the customary additives such as, for
`example, a nitroglycerin desensitization agent selected
`from the group consisting of a water soluble alcohol,
`glycerin and diethyleneglycol, flavoring and/or fra-
`grance materials, which are well known to those skilled
`in the art.
`
`The nitroglycerin spray according to this invention is
`manufactured by preparing a homogeneous one-phase
`solution of nitroglycerin, ethanol and l,2—propyleneg-
`lycol and filling it into an open mouth aerosol spray
`container, i.e. can or bottle, at a weight-% ratio such as
`stated in Table 2, a suitable dosing valve assembly is
`crimped or swaged on and the completed closed con-
`tainer is then charged with a mixture of dichlorodifluo-
`romethane and dichlorotetrafluoroethane at a weight-
`% ratio such as also stated in Table 2. The sealant mate-
`rials in the completed product have a nitroglycerin
`absorption value of less than 10 mg per one gram of
`sealant material. The container has a height of about 63
`mm and a diameter of about 22 mm. It provides about
`150 puffs. Table 1 provides pharmacokinetic parameters
`of various prior art nitroglycerin-containing sprays, as
`well as of a spray (Formula XS) according to the inven-
`tion, following sublingual application.
`Table 2 sets forth prior art spray formulations and a
`spray formulation according to this invention.
`The composition of a specific hydrophilic liquid
`spray according to this invention is as follows:
`
`SPECIFIC FORMULA XS
`AMOUNT IN GRAMS
`
`
`
` COMPONENT IN 100 G OF SOLUTION
`
`Nitroglycerin
`Ethanol
`l,2—Propyleneglycol
`Dichlorodifluoromethane
`Dichlorotetrafluoroetlrane
`Sealant material with an absorption
`value for nitroglycerin below
`10 mg/1 g of sealant material
`
`0.73
`13.83
`7.28
`31.26
`46.90
`
`5
`
`10
`
`According to the invention it has been discovered
`that the concentration of nitroglycerin in a liquid com-
`position can be maintained substantially steady or con-
`stant even if placed in contact with a sealant material by
`selecting a sealant material which has a nitroglycerin
`absorption value of less than 10 mg of nitroglycerin per
`one gram of sealant material.
`More specifically, the invention provides a product
`comprising a container having a liquid composition
`therein containing nitroglycerin, said container includ-
`ing a sealant material which absorbs less than 10 mg of 15
`nitroglycerin per one gram of sealing material. The
`container can include a valve assembly, the valve as-
`sembly including sealant means which has a nitroglyc-
`erin absorption value of less than 10 mg of nitroglycerin
`per one gram of sealant material. The container can
`include a suitable propellant which is effective for pro-
`ducing an aerosol spray of the liquid composition for
`medicinal purposes. The valve assembly can be of the
`type which provides a metered aerosol dose of the ni-
`troglycerin in the form of a puffer shot. The liquid
`composition desirably is hydrophilic.
`The sealant material is desirably a resilient polymeric
`material, and preferably a synthetic material. A sealant
`material which absorbs less than 10 mg of nitroglycerin
`per one gram of sealing material can be use in this inven-
`tion as a monolithic sealing material, meaning that it has
`essentially solid uniformity and constitutes one undiffer-
`entiated whole mass which may be a single polymeric
`material or a mixture of two or more closely related or
`different polymeric materials. Thus,
`it need not be
`coated with, or covered by, some other material before
`it is acceptable for use in the invention. Specifically
`undesirable as a sealant are TEFLON-type polymers
`used alone, or as a coating on some other sealant mate-
`rial, because TEFLON-type polymers absorb nitro-
`glycerin and swell when in contact with it.
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`20
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`25
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`
`FIG. 1 is a side elevational view of one embodiment
`of container which can contain a hydrophilic liquid
`composition including nitroglycerin and which con-
`tainer includes a conventional valve assembly capable
`of dispensing a metered aerosol puff or spray of the
`nitroglycerin active agent; and
`FIG. 2 is a vertical sectional view taken along the line
`2--2 of FIG. 1 and shows the valve assembly included
`in the container illustrated in FIG. 1.
`
`45
`
`50
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`According to a specific embodiment of the invention,
`a nitroglycerin aerosol spray is provided comprising a
`container having therein nitroglycerin, ethanol, 1,2-
`polyethyleneglycol, dichlorodifluoromethane and di-
`chlorotetrafluoroethane, present in certain weight ra-
`tios to one another and which is in essentially constant
`contact with a container sealant material, desirably a
`synthetic material, the absorption value of which for
`nitroglycerin is less than 10 mg/1 g of sealant material.
`The nitroglycerin spray according to this invention is
`desirably in the form of a nitroglycerin dosing pressur-
`ized aerosol-forming hydrophilic liquid, desirably com-
`posed of 0.73 weight-% nitroglycerin in a hydrophilic
`
`Hydrophilic liquid spray compositions provided by
`the invention will usually be within the following for-
`mulas:
`
`55
`
`
`BROAD FORMULA XB
`AMOUNT IN GRAMS
`COMPONENT
`IN 100 G OF SOLUTION
`
`
`Nitroglycerin
`Ethanol
`1,2-Propyleneglycol
`Diclilorodifluoromethane
`Dichlorotetrafluoroethane
`Sealant material with an absorption
`value for nitroglycerin below
`10 mg/1 g of sealant material
`
`65
`
`0.1 to 2
`2 to 20
`2 to 30
`10 to 40
`30 to 50
`
`

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`5
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`5,370,862
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`6
`When the container is filled and not in use the internal
`pressure causes the plug 26 to lift upwardly so that
`liquid fills the space in the valve body 22 above plug 26.
`When a metered dose is to be administered the top of
`stem 30 is pushed down causing the lower end of the
`stem to force plug 26 into sealing position with the
`bottom of bore 28. This prevents liquid from flowing
`into bore 28 from the container body during the period
`when a metered dose is expelled as a puff or shot into
`the buccal area of a person’s mouth. Shortly after the
`plug 26 is pressed into sealing position as described, the
`holes 52 are positioned below valve seat 54 thereby
`permitting liquid to flow from bore 28 into the holes 52
`and then into hole 50 from which it exits as an aerosol
`metered puff.
`Table 3 shows the interaction of the critical valve
`component parts, that is the identified sealants and a
`liquid spray composition therein according to this in-
`vention. Absorption of the active agent into the resilient
`polymeric monolit sealant material was determined by
`quantification of the nitroglycerin following its extrac-
`tion from the valve sealant material after a two or four
`week storage period in contact with the spray solution.
`The WE number (Table 3) is an identity number of
`the valve from which the respective sealing material
`was taken. During manufacture of the spray solution
`according to the invention, a specified amount of seal-
`ant material was added to the solution of active agent in
`the spray container, a valve was crimped on, the con-
`tainer charged, and the spray stored upright under the
`appropriate condition. At the time of testing, the spray
`container was discharged or emptied in a cooled condi-
`tion, the sealant material removed, washed, and the
`nitroglycerin content determined after the extraction.
`The tests resulted in the values shown in Table 3.
`The nitroglycerin (GTN) absorption at 20° C.
`amounts to 53 mg GTN/1 g sealant No. 400; 45 mg
`GTN/ l g buna BA 170 T.; 3.4 GTN/1 g neoprene beige
`and él mg GTN/1 g butyl FA 7500. Neoprene is a
`polymer produced from 2-chloro-butadiene and is avail-
`able from Dupont, Wilmington, Del; butyl FA 7500 is
`supplied by Action Technology S.p.A., IT-20063 Gag-
`giano (MI), Via Alessandro Volta 76, Italy, which also
`has factories in Rockaway, N.J., Clinton Ill. and Ana-
`heirn, Calif.
`Neoprene beige is available from Action Technology
`under the tradename Neopren AK/B. However, not all
`neoprene polymers are suitable. Thus, Neopren K3G, a
`type of neoprene, available from Action Technology is
`not suitable in the spray container of this invention.
`Valves with sealant materials having an absorption
`value greater than 10 mg/1 g sealant material, following
`storage in contact with the spray, led to an active agent
`reduction in the package such that the active ingredient
`content per individual dosage fell below the limits of the
`guidelines accepted by the German Pharmaceutical
`Law Code. Furthermore, valve assemblies with these
`strongly absorbing sealant materials, in the area of the
`dosing chamber, have contact with the next dose to be
`dispersed,
`thus further leading to unacceptably low
`dosage concentrations.
`Tables 4 and 5 show this absorption phenomenon at
`four charges of sprays which had been manufactured
`with valve assemblies containing different sealant mate-
`rials. The tables report the amount of active agent as a
`percent of the predetermined or set dosage amount in
`the first, second and third individual spray shots or puffs
`following varying nonuse time intervals. Only valve
`
`
`
`BROAD FORMULA XC
`WEIGHT PERCENT
`
`COMPONENT
`
`Nitroglycerin
`Ethanol
`1,2-Propyleneglycol
`Dlchlorodifluoromethane
`Dichlorotetrafluoroethane
`Sealant material with an
`absorption value for nitro-
`glycerin below l0 mg/l g of
`sealant material
`
`0.1 to 2
`2 to 60
`2 to 60
`10 to 50
`30 to 70
`
`The hydrophilic liquid spray composition in the fin-
`ished product is in contact with the container sealant
`material, and particularly the dosage metering valve
`materials.
`
`Stability investigations of sprays with identical con-
`tents according to this invention, identical containers,
`but qualitatively different valve assemblies revealed
`that the pharmaceutical quality of the product is only
`maintained by the use of valve assemblies which have
`been manufactured of specific sealant materials in
`which no, or only a tolerable, absorption of the nitro-
`glycerin occurs in the valve assembly component parts.
`Referring now to the drawings, FIG. 1 illustrates a
`finished product 10 according to the invention. The
`product 10 includes an open-mouth container body or
`preform 12 on which a valve assembly 14 has been
`attached by crimping or swaging. It should be under-
`stood that the invention is not limited to use of any
`particular container or valve assembly. The specific
`embodiment illustrated by the drawings is presented to
`show where sealant materials are located in such spray
`products and thereby contact the liquid nitroglycerin
`product.
`The valve assembly 14 is shown in vertical cross-sec-
`tion in FIG. 2. The valve assembly 14 includes a cup 16
`which has a vertical cylindrical skirt 18 and a top 20.
`Valve body 22 fits within the cup 16. A tube or stand-
`pipe 24 fits within the lower end of valve body 22 and
`extends to adjacent the bottom of the container body 12.
`A vertically displaceable loosely positioned plug 26 is
`located within an axial bore 28 in valve body 22. The
`plug 26 is made of a resilient sealant material so that it
`can seal readily with the bottom of axial bore 28 in
`valve body 22 when a metered dose is being expelled.
`Valve stem 30 has a lower solid portion 32 which fits
`into bore 28. A spring 34 is positioned between the wall
`of bore 28 and the surface of stem portion 32. The
`spring 34 presses against the stem flange 56 and against
`a ledge near the bottom of the bore 28. A gasket 38,
`which is L-shaped in section, fits securely against the
`valve body 22 and the outwardly projecting flange 40
`contacts the valve body 22 to provide a fluid tight seal.
`The gasket 38 is made of sealant material.
`The upper end of valve stem 30 has a vertical axial
`hole 50 and a pair of horizontal holes 52 which pene-
`trate the wall of the stem into communication with the
`hole 50. A valve seat 54, made of sealant material, is
`located in the too 20 so as to be around the stem 30
`upper portion. It prevents upward movement of the
`stem 30 when the stem flange 56 contacts the valve seat
`54. Such contact provides the ultimate seal which pre-
`vents escape of fluid from the container after it is filled,
`such as to an internal pressure of 4 bar, and is not in use.
`The two horizontal holes 60 are used to fill the con-
`tainer with propellant.
`
`l0
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`

`
`5,370,862
`
`7
`assemblies which contain butyl FA 7500 and neoprene
`provided acceptable pharmaceutical quality.
`Thus, practical dispensing of the pharmaceutical
`agent requires the use of dosage valve assemblies which
`employ specific sealant materials.
`Furthermore,
`the varying distribution coefficient
`(Pu) of nitroglycerin between the components of the
`pharmaceutical formulation (R) and the hydrophilic
`oral mucosa (M)
`where
`
`Pu = -22-
`
`is larger in the case of the hydrophilic formulation than
`in the case of a lipophilic formulation, through which
`the fast surge in vivo is achieved, is decisive.
`The distribution
`
`Pk = % (sealant = D),
`
`5
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`8
`this invention acts fast and effectively. Associated with
`this fast action is an earlier arrest of the angina pectoris
`attack and a rapid relief for the patient in this life threat-
`ening situation fraught with mortal terror.
`Two differently formulated nitroglycerin sprays
`were compared with one another using the same
`method of administration.
`The test spray (T) is a spray having the specific com-
`position set forth above according to this invention with
`10 the specific sealant material, which contains the active
`agent in a hydrophilic solution. The reference spray (R)
`contains the active agent in a lipophilic solution. Table
`6 shows the result of the testing.
`
`15
`
`Parameter
`
`Cm [pg/ml]
`tmw, [min]
`AUC [pg
`20 min/ml]
`
`TABLE 6
`T
`
`R
`
`1774 i 1272
`4.4 t 1.4
`9488 : 5303
`
`884 i 693
`7.9 i 2.8
`6990 : 5168
`
`T/R
`
`2.16
`
`1.52
`
`P
`
`0.006
`<0.05
`n.s.
`
`that is, in identical sealants is then larger in the case of
`the hydrophilic sprays and necessitates the use of new,
`specific sealant materials which have a low solubility,
`or a lower absorption, for nitroglycerin.
`In a bio-availability study and in a clinical study, the
`intended faster surge of the active agent with the nitro-
`glycerin dosage spray according to this invention was
`documented and the faster effect shown, as compared to
`the slower lipophilic spray.
`Of significance therapeutically is a fast surge (tmax) to
`high active agent concentrations. The medication of
`
`25
`
`30
`
`The test results reported in Table 6 reveal that the
`active agent from the test preparation was absorbed
`significantly faster than from the reference spray; Cm,
`was higher by the factor 2.2, and tmax was shortened
`from 7.9 to 4.4 min.
`
`The spray according to this invention provides a
`pharmaceutical product of good quality and which
`produces a fast surge of the active agent. For an angina
`pectoris patient, this means a faster effect and an earlier
`alleviation or removal of the anxiety state which occurs
`during an attack.
`
`TABLE 1
`
`Summary of Pharmacokinetic Parameters of Various Nitroglycerin Sprays Following
`Sublingl Application
`Number of
`Cm“
`Tests
`Dose (pg/ml)
`3
`0.4
`1. 400
`2. 860
`3. 590
`1. 2260
`2. 1620
`3. 1444
`670 1 500
`
`t,,,,,,,
`(min)
`4-5
`3
`5
`3.2
`6.5
`10.0
`10.0
`
`AUC
`(min pg/ml‘1)
`—
`
`—
`
`5740 i 4590
`
`rel. AUC
`(%)
`
`56.26
`
`58.9
`
`100
`
`36.5
`
`100
`
`36.9
`
`100
`
`73
`
`100
`
`Drug
`Lipophilic
`Spray A
`
`Lipophilic
`Spray B
`
`Source No.
`(See Footnotes)
`1A
`
`IB
`
`3
`
`0.4
`
`2
`
`2
`
`3
`
`3
`
`4
`
`'4
`
`5A
`
`SB
`
`12
`
`12
`
`8
`
`8
`
`12
`
`12
`
`24
`
`24
`
`0.8
`
`0.8
`
`0.8
`
`0.8
`
`0.8
`
`0.8
`
`0.4
`
`0.4
`
`760 :1: 450
`
`1150 i 770
`p < 0.05
`780 i 850
`
`3810 t 2810
`
`340 i 234
`
`1387 -J: 630
`p < 0.001
`884 i 693
`
`1774 i 1272
`p = 0.006
`
`8.0
`
`6360 i 3970
`
`8.0
`p > 0.05
`7
`
`9990 i 8080
`p < 0.05
`1369 t 16040
`
`4
`
`8.3 i 2.0
`
`4.3 i 1.6
`p < 0.05
`7.9 i 2.8
`
`37460 -.1: 14640
`< 0.05
`3516
`
`9534
`p < 0.001
`6990 i 5158
`
`4.4 i 1.4
`p > 0.05
`
`9488 i 5303
`Insignificant
`
`2
`
`12
`
`0.8
`
`Lipophilic
`Spray C
`Lipophilic
`Spray D
`Lipophilic
`Spray B
`Lipophilic
`Spray A
`Hydrophilic
`Spray A
`Lipophilic
`Spray B
`I-Iydrophilic
`Spray B
`Lipophilic
`Spray B
`Spray according
`to this
`Invention
`Formula XS
`TABLE 1 - FOOTNOTES
`1A. Nitrclingual Spray from 1982 produced by German firm Pohl Boskamp Company.
`1B. New formulation of the Nitrolingual Spray from Pohl Boskamp Company.
`2. Data from P. M. Dewland et al. Her: and Gegasse, 7, 536-544 (1987).
`3. Data from H. Laufen et al in Tlierapiewoclie 34, 963-970 (1984).
`4. Data from S. W. Sanders et al J. of Pharmaceutical Sciences, 75, 244-246 (1986).
`5A. Nitrolingual Spray of Pohl Boskamp Company (same spray as 18).
`SB. Spray according to the invention - Formula XS.
`
`

`
`9
`
`5,370,862
`
`10
`
`TABLE 2
`
`Spray Formulations
`
`
`
`Drug
`Source No.
`
`Lipophilic
`Spray A
`1
`
`Lipophilic
`Spray B
`1
`
`Hydrophilic
`Spray A
`3
`
`Hydrophilic Spray B
`Dictionnaire
`Vidale 1987
`
`Spray according to this
`Invention
`Formula XS
`
`Grams
`Grams
`M1
`Grams
`
`Components
`in 100 g
`in 100 g
`in 100 ml Components
`in 100 g
`Nitroglycerin
`0.9
`0.7
`34 ml
`Nitroglycerin
`14.56
`5% w/W
`in Ethanol
`
`Hydrophilic
`water miscible
`pump spray
`
`Nitroglycerin
`4% W/W
`in ethanol
`
`Neutral oil
`(1)
`Paraffin
`oil-viscous
`Ether
`
`27
`
`15.0
`
`12.4
`
`2.2
`
`-—
`
`1.8-
`
`Fragrance
`Propellant
`
`0.5
`57.0
`
`0.4
`82.1
`
`Ethanol 95%
`V/V
`Diethyleneg1ycol-
`monoethylether
`Fragrance
`Dichlorodifluoro-
`methane
`
`1,2-Propylene-
`glycol
`
`7.28
`
`14 ml
`
`1 ml
`
`1 ml
`50 ml
`
`31.26
`
`Dich1orodifluoro-
`methane
`46.90
`Dichlorotetra-
`fluoroethane
`(1) Miglyol 812 - Neutral oil; contains the nitroglycerin.
`
`TABLE 3
`Absorption of Nitroglycerin Into Various Sealant Materials
`From a Spray (1) of This Invention
`|mg Nitroglycerin/1 g Sealant
`Storage Conditions
`40° C.
`20° C.
`2 Weeks
`4 Weeks
`51.0
`44.5
`
`30
`.
`
`
`TABLE 3-continued
`Absorption of Nitroglycerin Into Various Sealant Materials
`From a Spray (1) of This Invention
`m Nitro
`cerin/1
`Sealant
`Storage Conditions
`20° C.
`40° C.
`20° C.
`40° C.
`
`Sealant Material
`2 Weeks
`2 Weeks
`4 Weeks
`4 Weeks
`(from valve WE
`1007/1008)
`Neoprene, beige
`35 (from valve WE 1031)
`Butyl FA 7500
`(from valves WE
`
`1123, 1124, 1125)
`
`1.5-7.5
`
`6.9-7.5
`
`3.4
`
`—
`
`——
`
`0.05-0.07
`
`13.0
`
`——
`
`40° C.
`4 Weeks
`49.0
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`14.6
`
`15.2
`
`(” F°“‘“’’‘’ XS
`
`
`TABLE 4
`
`Sealant Material
`Buna BA 170T
`(from valve WE 947)
`Seal No. 400
`(from valve WE 999)
`,B 470 PA
`(from valve WE 1010)
`RP 3-49-16
`(from valve WE 1008)
`Neoprene, black
`
`20° C.
`2 Weeks
`45.0
`
`53.2
`
`56.3
`
`44.0
`
`11.4
`
`61.1
`
`53.6
`
`49.0
`
`14.3
`
`Nitroglycerin Per Spray Dosage i.e. Puff or Shot
`Spray (1) According
`Spray (1) According
`to the Invention
`to the Invention
`Product Composition
`Spray 1
`Spray 2
`Product Number
`Butyl FA 7500
`Neoprene, free of carbon
`Sealant Material
`Nitroglycerin [%]/Three
`Nitroglycerin [%]/Three
`Storage Time
`After Manufacture
`Spray Puffs
`Spray Puffs
`
`and Priming (1) [Weeks]
`1st.
`2nd.
`3rd.
`1st.
`2nd.
`3rd.
`A 74.5
`83.2
`89.1
`A
`76.0
`93.3
`99.5
`B
`75.7
`87.8
`91.6 I
`B
`78.2
`92.0
`97.5
`C
`71.8
`91.3
`96.4
`
`2.5
`Storage Time
`2 Terms
`[Weeks]
`1
`
`OU.'J>Ot:u>O!:u>
`
`A 86.4
`B
`83.8
`
`A 85.2
`B
`83.1
`
`A 83.8
`B
`98.9
`
`94.8
`92.2
`
`92.0
`96.7
`
`98.7
`98.0
`
`99.0
`98.9
`
`100.7
`98.0
`
`102.5
`97.2
`
`86.9
`86.9
`82.6
`76.9
`79.4
`80.9
`62.2
`58.9
`64.4
`
`96.8
`98.9
`94.3
`93.4
`92.0
`90.2
`85.2
`81.4
`91.6
`
`100.0
`100.0
`99.8
`96.7
`96.3
`99.2
`99.2
`93.8
`99.6
`
`3
`
`10
`
`Storage conditions: 20-25‘ C. 40-60% relative humidity (1) Formula XS
`Nitroglycerin [%]/spray puff refers to the nitroglycerin content/spray puff or shot, which was
`determined as a constant value after multiple valve emissions. See Table 5.
`A. B, C = symbol for the spray container
`(1) Priming means to load the valve and have the product contact the gasket and be ready to spray
`a dose or puff.
`
`

`
`11
`TABLE 5
`
`5,370,862
`
`12
`
`Nitroglycerin Per Spray Dosage i.e. Puff or Shot
`Spray According
`Spray According
`to the Invention
`to the Invention
`Spray 1
`Spray 2
`Buna BA 170T
`Sealant No. 400
`Nitroglycerin [%]/Three
`Nitroglycerin [%]/Three
`Spray Puffs
`Spray Puffs
`1st.
`2nd.
`1st.
`2nd.
`A 56.3
`85.0
`69.7
`77.4
`B
`55.6
`80.9
`72.0
`82.0
`69.3 —
`
`Product
`Ch.-B.
`Sealant Material
`Storage Time
`After Manufacture
`and Priming [Weeks]
`4
`
`Storage Time
`2 Terms
`[Weeks]
`1
`
`3
`
`10
`
`3rd.
`81.2
`86.2
`86.8
`
`85.3
`82.3
`
`3rd.
`92.1
`94.1
`
`A
`B
`C
`
`A
`B
`
`65.0
`51.5
`
`75.2
`69.1
`
`94.2
`83.5
`A 54.0
`98.5
`82.5
`B
`59.5
`94.1
`81.8
`A 48.8
`104.9
`87.7
`B
`48.8
`Seal No. 400:
`92.7
`87.7
`A 63.5
`B
`51.8 — 95.3 A nitrogen content of
`100%/spray puff is
`reached from about
`15th spray puff on
`
`Storage condition: 20-25' C./40-60% relative humidity
`Nitroglycerin [%]/spray puff refers to the nitroglycerin content/spray puff or shot, which was
`determined as a constant value after multiple valve emissions.
`A, B, C = symbol for the spray container.
`
`What is claimed is:
`1. An aerosol spray including a closed container hav-
`ing a liquid composition therein comprising 0.1 to 2
`weight percent of nitroglycerin, 2 to 60 weight percent
`of ethanol, 2 to 60 weight percent of l,2-propyleneg-
`lycol, 10 to 50 weight percent of dichlorodifluorometh-
`ane and 30 to 70 weight percent of dichlorotetrafluoroe-
`thane, the container having a valve assembly sealed to
`the container around an opening in the container by a
`monolithic resilient polymeric sealant material selected
`from the group consisting of butyl FA 7500 and neo-
`prene free of carbon.
`2. An aerosol spray according to claim 1 comprising
`0.73 weight percent of nitroglycerin, 13.83 weight per-
`cent of ethanol, 7.28 weight percent of l,2-propyleneg-
`lycol, 31.26 weight percent dichlorodifluoromethane
`and 46.90 weight percent dichlorotetrafluoroethane.
`3. An aerosol spray according to claim 1 containing a
`pharmaceutically acceptable nitroglycerin desensitiza-
`tion agent.
`4. An aerosol spray according to claim 1 containing a
`nitroglycerin desensitization agent selected from the
`group consisting of a water soluble alcohol, glycerin
`and diethyleneglycol.
`5. An aerosol spray according to claim 1 in which the
`sealant material comprises a gasket between the valve
`assembly and the container.
`6. An aerosol spray according to claim 1 in which the
`sealant material comprises a gasket between the valve
`assembly and the container and the valve assembly has
`a manually operable spray valve for spraying a metered
`dosage of nitroglycerin in aerosol form into the mouth
`of a patient.
`7. An aerosol spray according to claim 1 in which the
`liquid composition in the container is in essentially con-
`stant contact with the sealant material.
`8. An aerosol spray including a closed container hav-
`ing a hydrophilic liquid composition therein comprising
`
`30
`
`35
`
`45
`
`50
`
`55
`
`60
`
`65
`
`0.1 to 2 g of nitroglycerin, 2 to 20 g of ethanol, 2 to 30
`g of 1,2-propyleneglycol, 10 to 40 g of dichlorodifluoro-
`methane and 30 to 50 g of dichlorotetrafluoroethane,
`per 100 g of liquid composition, the container having a
`valve assembly sealed to the container around an open-
`ing in the container by a monolithic resilient polymeric
`sealant material selected from the group consisting of
`butyl FA 750