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`
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`
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`
`AQUESTIVE EXHIBIT 1048 page 0001
`
`

`

`1
`
`4,690,952
`
`PHARMACEUTICAL COMPOSITIONS FOR
`NASAL ADMINISTRATION COMPRISING
`CALCITONIN AND AN
`ABSORPTION-PROMOTING SUBSTANCE
`
`BACKGROUND OF THE INVENTION
`
`1. Field of the Invention
`The present invention relates to a intranasal pharma-
`ceutical composition comprising calcitonin as an active
`ingredient and more particularly, to an excellent calci-
`tonin intranasal composition containing a specific ab-
`sorption enhancer.
`2. Description of the Related Art
`Calcitonin is a polypeptide hormone having various
`pharmaceutical activities which is used for treatment of
`osteoporosis, hypercalcemia, Paget’s disease, etc.
`Calcitonin is decomposed in the gastrointestinal tract
`by digestic juice, like ordinary pharmacologically ac-
`tive peptides so that oral administration of calcitonin is
`not available therapeutically. In addition, due to poor
`absorption, calcitonin is generally administered by in-
`jection. However, injections are extremely painful and
`this route of administration is not used.
`
`Thus inconvenience and a cost problem is encoun-
`tered.
`
`Recently, it has been found that by application of
`calcitonins via intranasal route, effects similar to con-
`ventional
`intramuscular injection are exhibited and,
`various compositions of intranasal calcitonin composi-
`tion have been proposed. However, a polypeptide hav-
`ing a large molecular weight such as calcitonin is ab-
`sorbed intranasally only with difficulty. Therefore, as
`absorption enhancers,
`for example,
`surface active
`agents are generally incorporated (Published Unexam-
`ined Japanese Patent Application Nos. 89691/84 and
`130820/84). In this case, both amphoteric and cationic
`surface active agents are employed; it is said, however,
`that nonionic type surface active agents, inter alia, poly-
`oxyethylene lauryl ether, are particularly excellent in
`absorption acceleration properties. However, this poly-
`ether type surface active agent exhibits the undesirable
`property of destroying the nasal membrane. Thus, the
`surface active agent has a strong toxicity to tissue and is
`therefore undesirable for use as it is.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`As a result of extensive investigations of dosage forms
`for intranasal administration capable of enhancing ab-
`sorption of calcitonin and providing for practical use,
`the present inventors have found that excellent results
`can be achieved by incorporating a certain absorption
`enhancer into the calcitonin-containing intranasal medié
`cal composition. The present invention relates to a in-
`tranasal medical composition comprising (a) calcitonin
`and (b) at least one absorption enhancer selected from
`the group consisting of benzyl alcohol, ethanol, thia-
`mine or a salt thereof, salicylic acid or a salt thereof,
`capric acid or a salt thereof, Macrogol 400, pyridoxal or
`a salt thereof, malic acid or a salt thereof and pyrophos-
`phoric acid or a salt thereof, which are contained in a
`liquid dilution or a carrier suitable for applying to nasal
`membrane.
`
`As calcitonins used in the present invention, various
`kinds of calcitonins such as salmon calcitonin, human
`
`2
`calcitonin, elcatonin, porcine calcitonin, etc. can be
`used.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`60
`
`65
`
`The substance that enhances absorption of calcitonins
`is selected from benzyl alcohol, ethanol, thiamine, sali-
`cylic acid, capric acid, Macrogol 400*, pyridoxal, malic
`acid and pyrophosphoric acid. Among these absorption
`enhancers, compounds capable of forming salts may be
`used in the form of the salts thereof. In the case of basic
`compounds such as pyridoxal, thiamine, etc., the hydro-
`chloride, the nitrate, etc. are employed. In the case of
`acidic substances such as pyrophosphoric acid, salicylic
`acid, malic acid, capric acid, etc., the sodium salts, po—
`tassium salts, etc. are employed.
`‘polyethylene glycol 400
`The absorption enhancers may be used singly or in
`combination of two or more other enhancers.
`The pernasal composition of the present invention
`may be in the form of an aqueous solution, hydrogel or
`solid powders.
`The aqueous solution is prepared by dissolving calci-
`tonins and the absorption enhancers in water or a buffer
`solution in a conventional manner. In this case, addi-
`tives are added to and dissolved in the aqueous solution,
`if necessary. It is preferred that pH of the aqueous solu-
`tion is between 3 and 5 in View of stability.
`As the buffer, citrates,
`tartarate, malates, etc. are
`employed, in a preferred pH range of 3 to 5.
`As the additives, sterilizers, preservatives, tackifiers,
`surface active agents, stabilizers, etc. conventionally
`used for pernasal agents can be incorporated.
`As the sterilizer and the preservative, conventional
`ones may be used and examples include p-oxybenzoates,
`propylene glycol, benzetonium chloride, sorbic acid
`(Na), etc.
`As the tackifier, polyvinyl alcohol, polyvinyl pyrrol—
`idone, dextran, etc. may be employed.
`The surface active agent is added as a dispersing and
`emulsifying agent for various additives; nonionic sur-
`face active agents that have little irritation to the mem-
`brane are preferred. As these nonionic surface active
`agents,
`for example, polyoxyethylene monostearate,
`polyoxyethylene sorbitan monooleate, polyoxyethy-
`lene-hydrogenated castor oil, etc. are used.
`As the stabilizer, mention may be made of gelatin or
`albumin.
`As the mode of administration, there may be used a
`method for dropwise addition or spraying using a drop-
`ping container, a sprayer or a nasal aerosol applicator
`for intranasal administration.
`In the case of a powdery form, mannitol, inositol,
`glucose, etc. are additionally added in a manner similar
`to the case of ordinary powders; after dissolving and
`then freeze-drying, the resulting solid is pulverized into
`fine powders, which are administered by a intranasal
`route. Such powders are administered in such a manner
`that they are packed in a capsule, the capsule is set in a
`spraying device and a needle is penetrated through the
`capsule to make pores at the top and the bottom of the
`capsule and air is sent via rubber balls, etc. to blow the
`powders out; etc. In case that volatile liquid compo-
`nents such as ethanol, benzyl alcohol, etc. are used as
`the absorption enhancers, the powdery form is not suit-
`able.
`.
`In the case of an aqueous gel, calcitonin is formed into
`an aqueous gel using gel bases conventionally used, for
`example, natural gums, methyl celluloses, acrylic poly-
`mers, vinyl polymers or polysaccharides, etc.
`
`AQUESTIVE EXHIBIT 1048
`
`page 0002
`
`AQUESTIVE EXHIBIT 1048 page 0002
`
`

`

`4,690,952
`
`3
`The proportions of calcitonin as an active ingredi-
`ents, the absorption enhancer and various additives to
`be used in the medical composition of the present inven-
`tion are not particularly limited but appropriately deter-
`mined depending upon dosage form of a solution, a gel
`or powders, etc. In case that the composition of calcito-
`nins for pemasal drops is in the form of an aqueous
`solution, calcitonin is formulated in a concentration of
`generally from 200 to 6000 IU/ml, preferably 500 to
`2000 IU/ml; the dose is preferably 0.05 to 0.2 ml/time
`and the number of administration is preferably 1 to 5
`times daily. Theamount of incorporated absorption
`enhancer varies but in the case of an aqueous solution, it
`is appropriate that the absorption enhancer be used in a
`range of 0.05 to 15% (w/v); a particularly preferred
`range is 1.0 to 10% (w/v) with respect to ethanol and
`0.1 to 5% (w/v) with respect to the other absorption
`enhancers;
`
`By the use of a specific absorption promoter in the
`calcitonin intranasal composition, efficiency of absorb-
`ing from the membrane of the nasal cavity is enhanced
`and it can be said that the calcitonin intranasal composi-
`tion is excellent.
`
`EXAMPLE AND EFFECTS
`
`10
`
`15
`
`20
`
`25
`
`Hereafter the present invention will be described in
`more detail with reference to the examples but is not
`deemed to be limited thereto.
`
`PREPARATION EXAMPLE 1
`
` per 1 m1
`Salmon calcitonin
`350 IU
`Citric acid hydrate
`12.2 mg
`Sodium citrate
`12.4 mg
`Absorption enhancer (cf. Table 1)
`
`
`30
`
`35
`
`4
`ample l were administered to the rats in a dose of 5
`IU/kg.
`Administration was performed by using a microsyr-
`inge (2 pl) having a connected a polyethylene tube (PE
`10, Clay Adams) therewith and injecting about 2 pl at a
`distance of 5 to 6 mm from the nasal septum depending
`upon the body weight. Evaluation of absorption of the
`calcitonin preparation through the nasal membrane was
`performed by measuring the concentration of calcium
`in serum. The calcium concentration was quantitatively
`determined using a calcium meter (CA-30, Joko). The
`rats were sacrificed prior to administration and 1, 2 and
`3 hours after administration,. Blood was collected from
`the descending large vein. The results are shown in
`Table 2. The data shown in Table 2 are mean values of
`3 or more rats.
`
`
`TABLE 2
`Concentration of Calcium in Serum
`after intronasal Administration of
`Calcitonin g5 lU/kg) Hours after
`Concen-
`Absorption
`tration
`________§§_EIg_%__
`
` enhancer % 1 2 3 hours
`
`
`
`
`a Control
`1
`10.65
`10.24
`10.81
`b Benzyl alcohol
`0.]
`9.01
`—
`11.17
`c Benzyl alcohol
`1
`8.41
`10.53
`10.73
`(:1 Ethanol
`5
`8.46
`11.12
`11.14
`e Malic acid
`3
`8.87
`11.59
`10.24
`1' Sodium caprate
`l
`8.67
`—
`-—
`g Sodium
`1
`8.56
`9.33
`10.7]
`salicylate
`h Macrogol 400
`i Thiamine
`hydrochloride
`j Pyridoxal
`hydrochloride
`k Sodium pyrophosphate
`1 Sodium pyrophosphate
`Thiamine
`hydrochloride
`—
`8.64
`—
`3
`in Sodium pyrophosphate
`
`Benzyl alcohol 1
`
`8.71
`8.48
`
`8.85
`
`8.97
`—
`
`11.24
`9.59
`
`—
`
`9.21
`8.68
`
`11.18
`11.37
`
`11.70
`
`9.84
`-—
`
`l
`1
`
`1
`
`3
`3
`3
`
`
` TABLE 1
`
`Absorption enhancer
`Amount (mg)
`a Control
`_
`b Benzyl alcohol
`1.0
`c Benzyl alcohol
`10
`d Ethanol
`50
`e Malic acid
`30
`f Sodium caprate
`10
`g Sodium salicylate
`10
`h Macrogol 400
`10
`i Thiamine hydrochloride
`10
`j Pyridoxal hydrochloride
`10
`k Sodium pyrophosphate
`30
`1 Sodium pyrophosphate
`30
`Thiamine hydrochloride
`30
`m Sodium pyrophosphate
`30
`
`Benzyl alcohol 10
`
`Salmon calcitonin and the absorption enhancer were
`dissolved in a solution of citric acid monohydrate and
`sodium citrate in a concentration twice that shown in
`the table, respectively. After pH was adjusted to 4.0
`using a 1N aqueous hydrochloric acid solution or a 1N
`aqueous sodium hydroxide solution, water is added to
`make 1 m1. Both are mixed in equal volumes. The sali-
`cylic acid preparation was a suspension. The sodium
`caprate preparation was adjusted to a pH of 8.
`EXAMPLE 1
`
`Sprague Dawley strain male rats (115-145 g) fasted
`for 18 hours were anesthesized with pentobarbital (50
`mg/kg, intraperitoneal injection). Aqueous calcitonin
`preparations a through m prepared in Preparation Ex-
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Calcium concentration in serum prior to administra-
`tion: 10.67 mg%
`From Table 2, it is noted that Ca concentration in
`serum is significantly reduced by the addition of a spe-
`cific absorption enhancer as compared to the control.
`In a manner similar to Preparation Example 1, calci-
`tonin intranasal compositions shown in the following
`preparation examples were prepared. These calcitonin
`solutions provide reduction of the calcium concentra-
`tion in serum as in Example 1.
`PREPARATION EXAMPLE 2
`
`Porcine calcitonin
`1400 IU
`Benzyl alcohol
`10 mg
`Malic acid
`13.4 mg
`Methyl p-oxybenzoate
`5 mg
`Propyl p-oxybenzoate 2 mg
`
`
`A IN aqueous sodium hydroxide solution was added
`to adjust pH to 4.0. Water was added to make the final
`volume 1 m1.
`
`PREPARATION EXAMPLE 3
`
`Elcatonin
`1400 IU
`Salicylic acid
`10 mg
`
`AQUESTIVE EXHIBIT 1048
`
`page 0003
`
`AQUESTIVE EXHIBIT 1048 page 0003
`
`

`

` -continued
`Benzetonium chloride
`0.1 mg
`Tartaric acid
`30 mg
`Hydroxypropyl cellulose
`20 mg ‘
`
`A IN aqueous sodium hydroxide solution was added
`to adjust pH to 4.0. Water was added to make the final
`volume 1 ml.
`
`PREPARATION EXAMPLE 4
`
`Salmon calcitonin
`1400 IU
`Macrcgol 400
`10 mg
`Thiamine hydrochloride
`10 mg
`Citric acid monohydrate
`12.2 mg
`
`Sodium citrate 12.4 mg
`
`Water was added to make the final volume 1 ml.
`
`PREPARATION EXAMPLE 5
`
`Salmon calcitonin
`14000 IU
`Sodium pyrophosphate
`300 mg
`Benzyl alcohol
`100 mg
`Benzetonium chloride
`1 mg
`Citric acid monohydrate
`122 mg
`
`Sodium citrate 124 mg
`
`15
`
`20
`
`25
`
`5N hydrochloric acid was added to adjust pH to 4.0.
`Water was added to make the final volume 10 ml.
`
`30
`
`PREPARATION EXAMPLE 6
`
`Salmon calcitonin
`14000 ID
`Sodium pyrophosphate
`300 mg
`D-Ribose
`300 mg
`Benzetonium chloride
`1 mg
`Citric acid monohydrate
`122 mg
`
`Sodium citrate 124 mg
`
`35
`
`40
`
`6
`enhancer selected from the group consisting of benzyl
`alcohol, ethanol, thiamine or a salt thereof, capric acid
`or a salt thereof, polyethylene glycol 400, pyridoxal or
`a salt thereof, malic acid or a salt thereof and pyrophos—
`phoric acid or a salt thereof which are contained in a
`liquid dilution or a carrier suitable for applying to nasal
`mucous membrane.
`
`2. An intranasal composition of calcitonin according
`to claim 1 wherein said absorption enhancer is thiamine
`or a salt thereof.
`
`3. An intranasal composition of calcitonin according
`to claim 1 wherein said absorption enhancer is pyro—
`phosphoric acid or a salt thereof.
`4. An intranasal composition of calcitonin according
`to claim 3 wherein said absorption enhancer is a salt of
`pyrophosphoric acid.
`5. An intranasal composition of calcitonin according
`to claim 1 wherein said absorption enhancer is benzyl
`alcohol.
`
`6. An intranasal composition of calcitonin according
`to claim 1 wherein said absorption enhancer is a combi-
`nation of thiamine or a salt thereof and pyrophosphoric
`acid or a salt thereof.
`
`7. An intranasal pharmaceutical composition of calci-
`tonin according to claim 1 wherein said absorption
`enhancer is ethanol.
`
`8. An intranasal pharmaceutical composition of calci-
`tonin according to claim 1 wherein said absorption
`enhancer is capric acid or a salt thereof.
`9. An intranasal pharmaceutical composition of calci-
`tonin according to claim 1 wherein said absorption
`enhancer is polyethylene glycol.
`10. An intranasal pharmaceutical composition of cal-
`citonin according to claim 1 wherein said absorption
`enhancer is pyridoxal or a salt thereof.
`11. An intranasal pharmaceutical composition of cal-
`citonin according to claim 1 wherein said absorption
`enhancer is malic acid or a salt thereof.
`
`4,690,952
`
`12. A method of administering a calcitonin to a sub-
`5N Hydrochloric acid'was added to adjust pH to 4.0.
`Water was added to make the final volume 10 ml.
`ject requiring calcitonin treatment, which method com-
`What is claimed is:
`prises administering to said subject requiring such treat-
`ment, from about 200 to about 6000 IU/ml of a compo-
`1. An intranasal pharmaceutical composition of calci-
`t
`it
`t
`t
`*
`tonin comprising (a) a pharmaceutically effective 45 sition as defined in claim 1 via the nasal route.
`amount of calcitonin and (b) at least one absorption
`
`50
`
`55
`
`60
`
`65
`
`AQUESTIVE EXHIBIT 1048
`
`page 0004
`
`AQUESTIVE EXHIBIT 1048 page 0004
`
`