Bibliographic data
`
`Title:
`
`Pub/Patno:
`
`Pub/Issue Date:
`Inventor(s):
`
`STABLE AQUEOUS SOLUTION CONTAINING
`DIPHENHYDRAMINE
`
`JPH01203320A
`
`1989-08-16
`KUROBE TOSHIO| TATEISHI KIMIO| OSAWA
`SHIGEMITSU|KUROBE TOSHIO|TATEISHI KIMIO |OSAWA
`SHIGEMITSU
`
`Applicant(s):
`Classification:
`
`EISAI CO LTD
`A61K9/08AT, AGIK31/135AI; A61K47/00AI;, A61K47/LOAT,
`A61K47/18AI; A61K47/26AI; A61K47/32AT; A61K47/42AT,
`A61P37/08AI;, A61P43/00AI
`Application number:—_JP 19880025506 1988-02-05
`Priority number:
`JP 19880025506 1988-02-05;
`
`Abstract of JPH01203320A
`
`PURPOSE:Toprovide the present aqueous solution having high stability to hydrolysis in acidic
`
`regions, by compounding polyvinyl pyrrolidone as an essential component.
`
`CONSTITUTION:0.01-10wt.% of polyvinyl pyrrolidone is compounded with an aqueoussolution
`containing 0.01-5wt.% of diphenhydramine at pH3-5. The further addition of 5-50wt.% of sorbitol
`
`and/or glycerol, 0.05-5wt.% of glycine and aspartic acid or 0.1-5wt.% of a water soluble
`
`polypeptide (e.g., gelatin hydrolyzate) improvesthe stability furthermore.
`
`

`

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`

`6/29/2020
`
`Espacenet- Bibliographic data
`
`Europalsches
`fitLily
`
`TELycul Espacenet
`
`Bibliographic data: JPH01203320 (A) — 1989-08-16
`
`STABLE AQUEOUS SOLUTION CONTAINING DIPHENHYDRAMINE
`
`Inventor(s):
`
`KUROBE TOSHIO; TATEISHI KIMIO; OSAWA SHIGEMITSU +
`(KUROBE TOSHIO, ; TATEISHI KIMIO, ; OSAWA SHIGEMITSU)
`
`Applicant(s):
`
`EISAl CO LTD + (EISAI CO LTD)
`
`Classification:
`
`- international: A61K31/135; A61K47/00; A61K47/10; A61K47/18;
`A61K47/26; A61K47/32; A61K47/42; A61K9/08;
`A61P37/08; A61P43/00; (IPC1-7): A61K31/135;
`A61K47/00; A61K9/08
`
`Application
`number:
`
`Priority
`number(s):
`
`- cooperative:
`JP19880025506 19880205
`
`JP19880025506 19880205
`
`Also
`published as:
`
`JP2617508 (B2)_
`
`Abstract of JPH01203320(A)
`
`PURPOSE:To provide the present aqueoussolution having high stability to hydrolysis
`in acidic regions, by compounding polyvinyl pyrrolidone as an essential component.
`CONSTITUTION:0.01-10wt.% of polyvinyl pyrrolidone is compounded with an aqueous
`solution containing 0.01-5wt.% of diphenhydramine at pH3-5. The further addition of 5-
`50wt.% of sorbitol and/or glycerol, 0.05-5wt.% of glycine and aspartic acid or 0.1-5wt.%
`of a water soluble polypeptide (e.g., gelatin hydrolyzate) improvesthe stability
`furthermore.
`
`https://worldwide.espacenet.com/publicationDetails/biblio?7II=O&ND=3&adjacent=true&locale=en_EP&FT=D&date=19890816&CC=JP&NR=H012...
`
`1/1
`
`

`

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`
`DESCRIPTION JPHO1203320
`
`[0001]
`TECHNICAL FIELD The present invention relates to a stable diphenhydramine-containing
`aqueoussolution. Therefore, the present invention is used in the field of pharmaceutical
`formulation technology. That is, the present invention is an invention of a formulation technology
`for providing an aqueous solution containing diphenhydramine having an antihistamine action
`and an antiallergic action, which is stable. (Prior Art) An aqueoussolution containing
`diphenhydramine has been conventionally prepared as an injection, a syrup, and an eye drop. In
`these preparations, it was a conventional technique that the pH of an aqueoussolution is
`generally adjusted to a neutral range. That is, as shownin the following documents(a)to (b), it is
`knownthat the stability of diphenhydramine significantly changes depending on the pH of the
`aqueoussolution, and therefore, in the preparation of the aqueous solution, a stable pH range,It
`is usually regulated in sex ptt regions 6-7. (A) Horiokaet al., Gathering, 11111.79 (1960) (b)
`Japanese Pharmacopoeia 10th Edition (Floor Bookstore) C427, Note 1 of "Diphenhydramine
`Hydrochloride". However, it may be necessary to adjust the pH of the diphenhydramine-
`containing aqueoussolution to an acidic liquid. O For example, in addition to diphenhydramine,
`other drugs such as scopolamine hydrobromideand atropine sulfate which are unstable in a
`neutral pH range are mixed. When necessary, it may be necessary to adjust the pH of the
`aqueoussolution to an acidic range based on the request of the drug. Also, when taken in a
`neutral pH range in a drink, diphenhydramine gives a bitter taste and a paralyzing sensation in
`the oral cavity, especially on the tongue, whichis relatively persistent and causes discomfort to
`the drinker. Become. This is because the dissolved type of diphenhydraminein the aqueous
`solution exists as € most molecular type diphenhydramine, and it can be reduced by decreasing
`the molecular type diphenhydramine amount,that is, by using dissociative diphenhydramine in
`the acidic pH range. it can. For these purposes,it may be desirable to adjust the po of the
`aqueous solution to an acidic range as long as the stability permits. However, the requirements in
`
`29-06-2020
`
`1
`
`

`

`these cases are inconsistent with the stability of diphenhydramine, especially with respect to
`hydrolysis, andit is clear from the above that the results are impaired. For this requirementto be
`possible, special means must be devised to increase the stability of diphenhydramine at pH in the
`acidic range. However, no special meansfor solving the above problems has been completed in
`the conventional techniques.
`
`[Problemsto be Solved by the Invention] As is clear from what has been described above, the
`problem to be solved by the present invention is to provide a special meansfor increasing the
`stability of diphenhydramineat pH 3 to 5, which is a pH in the acidic range.It is to be. [Means
`for Solving the Problems] With respect to the above problems, the present inventor has
`conducted various studies, and found that the above problems can besolved by blending
`polyvinylpyrrolidone as an essential component, thus completing the present invention. Came to
`do. Thatis, the present invention relates to a diphenhydramine-containing aqueous solution
`containing polyvinylpyrrolidone as an essential componentat pH 3 to 5. In the present invention,
`by blending polyvinyl pyrrolidone with glycerin and/or sorbitol, or one or more selected from
`glycine, aspartic acid and water-soluble polypeptide, it is possible to prevent hydrolysis at pH 3
`to 5. A morestable diphenhydramine-containing aqueous solution can be obtained. Furthermore,
`at pH 3 to 5, polyvinylpyrrolidone is blended as an essential component, and further, glycerin
`and/or sorbitol and one or more selected from glycine, aspartic acid, and water-soluble
`polypeptide are added to the aqueous solution containing diphenhydramine. Are more preferable
`in stabilizing against hydrolysis. The present invention will be described in detail below. In the
`present invention, diphenhydramine may be one that is commonly obtained as a drug for
`antihistamines, and may be usedin the form of a salt such as hydrochloride. Usually,it is orally
`administered, but 10 to 3 g of antihistamine is subcutaneously or intramuscularly administered,
`and 2% ointmentis externally applied. The amount of diphenhydramine in the aqueoussolution
`of the present invention is not particularly limited, but a concentration of 0.01 to 5% by weightis
`usually preferable in view of the fact that the present invention is used as a medicine. In the
`present invention, as polyvinylpyrrolidone, those available as PvPK-15, 30, 60, 90 (manufactured
`by GAF Corp) may be used. The amountof polyvinylpyrrolidone in the aqueoussolution of the
`present invention may be appropriately selected by experiments depending on the storage
`conditions required for the aqueous solution and the dosage form, but is preferably in the range
`of 0.01 to 10% by weight. Further, in the present invention, as sorbit and glycerin, those which
`are commonly available may be used, and the respective amounts in the aqueoussolution of the
`present invention are preferably in the range of 5 to 50% by weight. In the present invention, as
`glycine and aspartic acid, those which are commonlyavailable may be used (the respective
`amounts in the aqueoussolution of the present invention are preferably in the range of 0.05 to
`5% by weight).
`
`In the present invention, as the water-soluble polypeptide, egg white hydrolyzate, gelatin
`
`29-06-2020
`
`2
`
`

`

`hydrolyzate, etc. may be used. The amountof these in the aqueoussolution of the present
`invention is preferably in the range of 0.1 to 5% by weight. The pH of the aqueoussolution of the
`present invention is 3-5. In general, the adjustment of pH involves a measurementerror of about
`0.5 at maximum,and therefore the pH range should notbestrictly defined, and should be
`interpreted in the meaning of about 3 to 5 according to the technical problem of the present
`invention. .. A buffering agent is preferably added to avoid the occurrence of measurementerror.
`As the buffer, it is desirable to use, for example, a citrate buffer solution, a tartrate buffer
`solution, a phosphate buffer solution, or the like. The aqueous solution of the present invention
`may contain any drug other than diphenhydramine. Examplesof the drug other than
`diphenhydramine include scopolamine hydrobromide, atropine sulfate, chlorpheniramine
`maleate, pyridoxine hydrochloride, theophylline, 8-hydroxytheophylline and thelike. In addition
`to the diphenhydramine hydrochloride, the diphenhydraminesalicylate, tannate and the like can
`be freely added, and the aqueoussolution of the present invention is mainly used asa drink, an
`injection and an eye drop. Therefore, the production of the aqueoussolution of the present
`invention may becarried out according to a conventional method for each of these preparations.
`Also, in addition to the above-mentioned components, the aqueoussolution of the present
`invention contains conventional drinks, injections, and eye drops. Known additives used in the
`above may be added. [Working] The action of the aqueous solution of the present invention is the
`inhibition of hydrolysis, and is specifically shown by a decrease in the reaction rate constant of
`the hydrolysis reaction of diphenhydramine. Thatis, it is shown that the reaction rate constant at
`pH 3 to 5 is loweredbythe blending of polyvinylpyrrolidone or the blending of
`polyvinylpyrrolidone and glycerin and the like. [Examples] Hereinafter, the present invention will
`be described in more detail with reference to Examples, but the present invention is not limited
`to these Examples. Example 1 (injection) 3 g of diphenhydramine hydrochloride, 0.001 g of
`scopolamine hydrobromide, 0.1 g of polyvinylpyrrolidone (degree of polymerization 30), sorbit
`(crystal) ) 7 g are sequentially added anddissolved, and the total amount is made 100- to prepare
`an injection by a conventional method. Example 2 (eye drops) Diphenhydramine hydrochloride 1
`g 1 and atropine sulfate 0.001 g in 0.01 M phosphate buffer 90-pH 5.0. Polyvinylpyrrolidone
`(degree of polymerization: 30) 0.3 g, glycine 0.1 g, and sodium chloride 0.8 g are sequentially
`added and dissolved.
`
`If necessary, an antiseptic agent is added and the whole amountis closed to 100- to prepare an
`eye drop by a conventional method. Example 3 (drink) pH of 3.0, 0. To OIM tartaric acid buffer
`50-, 0.2 g of diphenhydramine hydrochloride, 0.5 mg of scopolamine hydrobromide,5 g of
`polyvinylpyrrolidone 1 g of aspartic acid 1 g of methyl paraoxybenzoate 10B, and 100 mg of
`flavor were sequentially dissolved to make 1501a1, and the total amount was 1501a1. To
`produce a drink. [Effects of the Invention] The present invention will be described in detail with
`referenceto the following experimental examples. Experimental Example 1 Formula-Material
`Diphenhydramine hydrochloride was dissolved in a 0.01 M citrate buffer solution having a pH of
`2,0,3,0,4,0,5,0 at a concentration of 0.1 g/100af, and polyvinylpyrrolidone, Add glycerin, sorbit,
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`aminoacids (glycine, alanine, aspartic acid) or water-soluble polypeptide (egg white hydrolyzate)
`to 1%, 40%, 40%, 0.1%, 0.1%, respectively. Then, the whole amountwas used as a specimen
`sample. Separately, a sample to which nothing was added wasprepared as a control sample. Each
`sample was heated at 120° C. for 20 minutes, and the residual amountof diphenhydramine
`hydrochloride was measured. In both cases, the decrease in the residual amount of
`diphenhydramine hydrochloride was observed in the form ofthe first-order reaction, and
`therefore the reaction rate constant K was determined by the following formula. K=2.303/t
`Xloga/(a— x)a=initial concentration (%) of diphenhydramine hydrochloride x=8 after
`concentration of hydrolyzed diphenhydramine hydrochloride (%) t=day (day) It showsin Table 1.
`The values in the table indicate reaction rate constants (day-’). From Table 1, it was found that by
`blending polyvinylpyrrolidone, glycine, aspartic acid, water-soluble polypeptide, glycerin or
`sorbit, hydrolysis of diphenhydramine hydrochloride was suppressed in p113 to 5.
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`
`CLAIMS JPHO1203320
`
`1.
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`5. An aqueous solution containing diphenhydramine, characterized in that polyvinylpyrrolidone
`is blended as an essential componentin 5. 2. A diphenhydramine-containing aqueous solution,
`which comprises polyvinylpyrrolidone as an essential componentat pH 3 to 5 and further
`glycerin and/or sorbit. 3. A diphenhydramine-containing aqueous solution, which is prepared by
`blending polyvinylpyrrolidone as an essential componentat pH 3 to 5, and further blending one
`or more species selected from glycine, aspartic acid, and a water-soluble polypeptide. 4,
`characterized in that polyvinylpyrrolidone is mixed as an essential componentat pH 3 to 5, and
`further glycerin and/or sorbit is mixed with one or more kinds selected from glycine, aspartic
`acid, and water-soluble polypeptide. An aqueous solution containing diphenhydramine.
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