(19) Japan Patent Office (JP)
`
`(12) Patent Gazette (A)
`
`(11) Japanese Patent Application Publication Number
`Hei 8 — 231391
`
`(43) Publication Date September 10, 1996
`
`(51) Int. Cl 6
`A61K 31/20
`
`Classification Symbol
`AAM
`
`Internal No.
`
`Technology Display Location
`FI
`A61K31/20 AAM
`
`Request for Review Unrequested Number of Claims 5 (Total 4 Pages)
`
`(21) Application Number
`(22) Application Date
`
`7 — 36362
`February 24, 1995
`
`(71) Applicant
`
`(71) Applicant
`
`(71) Applicant
`
`(72) Inventor
`
`(72) Inventor
`
`
`
`392030380
`Kanagawa Kagaku Kenkyuujo Co. Ltd.
`Kanagawa-ken, Sumohara-shi, Nishi
`Onuma 4 Choume 4 Ban 1 Go
`
`000173762
`Sumo Central Chemical Research
`Location Foundation
`
`Kanagawa-ken, Sumohara-shi, Nishi
`Onuma 4 Choume 4 Ban 1 Go
`
`592197599
`Fuji Yakuhin Co. Ltd.
`Saitama-ken, Omiya-shi, Sakuragi Machi
`4 Choume 383 Banchi
`
`Ichira Yasawa
`Kanagawa_l<en, Sumohara-shi, Kami-no-
`mori 1 — 28 — 10
`
`Miyanaga Kazuo
`Gunma-ken, Maebashi-shi, Kanne Machi
`3 — 5 — 29
`
`Continued on the last page
`
`(54) [Title of the Invention] Medicine for Improvement of Dementia Symptoms
`
`(5 7) [Abstract]
`[Objective] To smoothly improve the symptoms of
`dementia and provide a medicine for said improvement
`without side effects.
`
`[Structure] A medicine for improvement of dementia
`symptoms that has as a characteristic the inclusion of
`docosahexaenoic acid (DHA).
`[Effect] The medicine improves the following ailments
`caused by dementia: loss of will, delirium, worsening of
`human relationships, loitering, manic psychological
`episodes and/or the reduction of powers of calculation,
`reduction ofjudgment, and reduction in the intellectual
`capacities and fiJnctioning of the higher functions.
`
`Petition for Inter Partes Review
`Of U.S. Patent 8,278,351
`Exhibit
`
`ENZYMOTEC - 1015
`
`000001
`
`AKER877ITC00804518
`
`000001
`
`

`

`(2)
`
`Hei 8 — 231391
`
`[Scope of Claims]
`[Claim 1] A medicine for improvement of dementia symptoms
`being characterized by including as an active ingredient DHA.
`[Claim 2] A medicine for improvement of dementia symptoms
`of claim 1 that treats an adverse psychological state that is
`dementia.
`
`[Claim 3] A medicine for improvement of dementia symptoms
`of claim 2 working to reduce will loss, delirium, worsening of
`human relationships, manic states, and/or loitering.
`[Claim 4] A medicine for improvement of dementia symptoms
`of claim 1 working to reduce the loss of higher functions and of
`judgment brought about by dementia.
`[Claim 5] A medicine for improvement of dementia symptoms
`of claim 1 working to reduce the loss of intellectual capacity,
`loss of facilities of calculation, loss of judgment, and/or loss of
`higher function due to dementia.
`
`[Detailed Description of the Invention]
`[0001 ]
`[Industrial Field of Use] The present invention is in relation to a
`medicine for the betterment of mental symptoms that
`accompany dementia, and in particular relates to a medicine for
`the improvement of dementia symptoms that includes as an
`active ingredient DHA.
`[ 0002 ]
`[Related Art ] With the aging of society in recent years, the
`development of medicine for the treatment of dementia has
`become more important both medically and socially. For
`example, a dementia patient may suffer worsening family
`relationships as a result of loss of will, delirium, or trouble in
`interpersonal relationships, and the looking after of the patient
`within the family becomes difficult. This has been pointed out
`as the most serious cause for concern. In past years many
`medicines have been developed for dementia, but the results
`haven’t always been satisfactory. Furthermore, the traditional
`medicine can cause headache, dizziness, reduction in sex drive,
`emotional disturbances, and other side effects such as damage
`to the stomach.
`It is with this that there has been great
`expectation for the development of a new medicine for
`dementia.
`
`[ 0003 ] DHA is present in abundance in the brain and the thick
`mucus membranes. DHA is known to stop the functioning of
`arachidonic acid. Also, in addition to this, it is known that DHA
`contains several useful biological functions. For example, the
`following patent applications have been made: substance for
`the increase of brain function, medicine for the improvement of
`academic performance, medicine for improvement of memory,
`dementia prevention substance, substance for the treatment of
`dementia, and functional food that improves brain function (Hei
`2 — 49723), cholinergic agent (Hei 1 — 279830), agent for the
`treatment of thrombosis (Sho 57 — 35512), among others.
`Among these, patent application Hei 2 — 49723 shows that
`DHA can aid in the improvement of academic ability as well as
`increasing memory performance, and also acts to prevent the
`formation of platelet aggregation. However, this application
`said nothing more and did not hint at the specific application of
`DHA to dementia. Also, Application Hei 1 — 279830 is in
`relation to the increase of transmission volume to the brain of
`
`physostigmine, a cholinesterase antagonist, via the DHA.
`[ 0004 ]
`
`[Problem Solved by the Invention] The present invention
`provides a medicine to improve with the symptoms of dementia
`without providing side effects.
`[ 0005 ]
`[Method of Solving the Problem] The inventors of the present
`invention gave DHA, widely known for being a health food, to
`dementia patients, whereupon the symptoms of the dementia
`were immediately lessened, and based on that discovery
`gathered to file this application.
`[ 0006 ] In other words, the present invention provides a
`medicine for the improvement of dementia symptoms that
`includes DHA.
`
`[ 0007 ] The medicine for the improvement of dementia
`symptoms of the present invention is applied to psychological
`states accompanying dementia from multiple infarction, brain
`blood vessel function, brain damage, or Alzheimer’s disease
`(such as loss of will, delirium, worsening of human
`relationships, mania, loitering, etc.) or the reduction in
`intellectual capabilities (for example a reduction in the powers
`of calculation, a reduction in judgment, or a reduction in higher
`order functions).
`[ 0008 ] The DHA used in the present invention is an isolated
`acid, and refers to salt, ester, glyceride, phospholipids, choline
`compounds, ascorbic acid compounds, amino acid compounds.
`As for the oil that includes the DHA, an inclusion ratio of 10%
`or more DHA (as an isolated acid) within general fatty acids.
`As an example of such an oil, the fish oil extracted from blue
`backed fish such as Japanese pilchard, mackerel, horse
`mackerel, salmon, and Pacific saury, the fish oil from large
`ocean fish eye oil, such as that of the tuna or the shipj ack tuna,
`oil coming from microorganisms, krill oil, and oil from
`industrial products extracted from the livers of Pacific cod and
`dolphins.
`[ 0009 ] The medicine for the improvement of the symptoms of
`dementia of the present invention may be administered either
`orally or non-orally. For oral administration, powder, granule,
`capsule, lozenge, and other solid forms of administration are
`acceptable. Alternatively, the medicine may be administered as
`syrup, elixir, and other liquid forms. Also, for non-oral
`administration an injection can be given. By adding these forms
`of manufacturing to the approved medicine that is the active
`portion of the drug the medicine may be manufactured in the
`normal fashion. Furthermore, it is also possible to turn the
`medicine into extended release tablets via publicly known
`methods. When using those manufacturing helper substances
`the DHA levels within the medicine for the improvement of the
`symptoms of dementia of the present invention is between 10
`and 100 % by weight, and preferably between 50 and 100 % by
`weight.
`[ 0010 ] An appropriate manufacturing helper substance will be
`used in the above in accordance with the administration method,
`for example, internal use substances (oral medicine), injection
`use substances (injected medicine), adhesive administration
`substances (buccal, troche, and suppositories).
`[ 0011 ] For example, in oral and adhesive administration
`excipients (example: starch, milk sugar, crystal cellulose, milk
`calcium, metakei acid aluminum acid magnesium, waterless
`silicic acid), collapse agents (example: carboxymethylcellulose,
`carboxymethyl cellulose calcium), lubricants (example: sterin
`acid magnesium, talc), coatings (example: hydroxyl methyl
`
`000002
`
`AKER877ITC00804519
`
`000002
`
`

`

`cellulose, sugar, hydroxyl propyl cellulose ), and taste making
`agents, and other production substances may be used.
`[ 0012 ] In order to manufacture granules, wet or dry droplets
`are formed, and in order to produce pills, it is permissible to
`form the tablets with the powder and granules either left as they
`are or with additional stearic acid magnesium, talc, or other
`lubricant. These granules or tablets are coated with a stomach
`settling agent such as hydroxypropyl — methyl cellulose
`phthalate or methacrylic acid or methacrylic acid methyl
`copolymer, among others, and coating is made using stomach
`setting agent or ethyl cellulose, carnauba wax, hardened oil, or
`other substance. By doing so a durable pharmaceutical product
`may be produced. Also, in order to produce the medicine in
`capsule form, the powder or granules are filled into a hard
`capsule or the active ingredients are coated with a gelatin film
`either as is or after being melted into gelatin, polyethelyn glycol,
`sesame oil, olive oil, or other oil. In this way it is possible to
`generate a soft capsule.
`[ 0013 ] In order to produce liquid medicine for oral
`administration, the active ingredient and a sweetener such as
`refined sugar, sorbitol, glycerol are dissolved in water, a clear
`syrup, essential oil, and ethanol are added making an elixir-like
`medicine, or alternatively gum arabic, tragacanth gum,
`polysorbate 80, carboxymethyl cellulose (CMC), or another
`such substance is added and an emulsion or a suspension is
`produced. This is also acceptable. Flavor agents, color changing
`agents, and/or preservatives may be added to the liquid
`solutions discussed herein, according to taste.
`[ 0014 ] Also, stable production medicine components are used
`for inj ectable medicine, such as solution from water soluble
`inj ectable medicine and melted helper substances (example
`injection use distilled water, biological salt water, or propylene
`glycol), suspension substances (example: polysorbate 80 or
`other surfactant), pH regulation substances (example: organic
`acid or its metal salt).
`[ 0015 ] In order to produce inj ection-use medication, the active
`ingredients are mixed with salts, sodium hydroxide, emulsion,
`emulsion natrium, dibasic sodium phosphate, sodium
`dihydrogen-phosphate, and other pH adjusting agents, sodium
`chloride, grape sugars, and other tonicity adjusting agents in
`injection use distilled water. The solution is sterilized and
`poured into an ampoule. Alternatively, mannitol, dextrin, cyclo-
`dextrin, gelatin, and other substances are added, fired into
`crystals under vacuum conditions, and placed into a form to be
`melted at the time of injection. To the active ingredients are
`added lecithin, polysolvent 80, polyoxyethylene hydrogenated
`castor oil, and other substances, melted into water and made
`into an inj ectable solution.
`Table 1. Level of Improvement in Psychological State
`Recovered
`Somewhat
`Recovered
`
`[ 0016 ] Additionally, water or oil soluble medicines or soluble
`helper substances (example: alcohol, fatty acid esters),
`adhesives (example: carboxy vinyl polymer multi-sugars),
`emulsifiers (example: surfactants), and other substances are
`used as ingredients in externally administrable medicine. In
`producing rectally administered medicine the active ingredients
`and cocoa butter, fatty acid salts, mono glycerides and other
`suppository use substances are humidified, melted, poured into
`a mold, hardened, and frozen. Alternatively, the active
`ingredient could be melted in polyethylene glycol, soybean oil,
`or other oil, and thereafter coated in a gelatin film.
`[ 0017 ] Additionally, the medicine for the improvement of
`dementia symptoms of the present invention with the above
`listed characteristics may be produced using publicly known
`manufacturing methods, for example as stipulated in version 10
`of the Pharmacy Act of Japan, noted in the manufacturing
`addendum, or a method that has appropriately modified the
`aforementioned method.
`
`[ 0018 ] In particular, the medicine for the improvement of
`dementia of the present invention administration of a high
`purity concentration of DHA (for example, 90% or above) via a
`soft capsule is desirable because of the ease of administration.
`[ 0019 ] The amount of DHA administered in the medicine to
`prevent the symptoms of dementia of the present invention will
`vary based on the body weight and health conditions of the
`patient, but in general, the dose will range from 100 to 2000 mg
`/ person with between one and several administrations per day.
`[ 0020 ] Below we explain the present invention in detail by
`following an embodiment of the present invention.
`[0021 ]
`[Embodiments]
`Embodiment 1. Test to measure level of psychological
`improvement
`The targets of this test were 13 cranial blood vessel related
`dementia patients and 5 Alzheimer’s related dementia patients.
`In addition to traditional treatments, 10 — 20 capsules including
`70 mg of DHA each were administered (hereinafter referred to
`as the “DHA Administration Group”), and the results of the test
`were compared before administration and 6 months after
`administration. Also, a group that continued traditional
`pharmaceutical treatments (hereinafter referred to as the
`“Unchanging Administration Group”; 24 individuals) were
`targeted for the same test and the variance from the DHA
`Administration Group was observed. The results appear in
`Table 1.
`
`[ 0022 ]
`[Table 1]
`
`
`
`Cranial Blood Vessel
`Dementia
`Alzheimer’s Dementia
`
`No Change Worsened
`
`000003
`
`AKER877ITC00804520
`
`000003
`
`

`

`[ 0023 ] To further break down the content of the
`“improvements” seen in the cranial blood vessel related
`dementia patients, 2 cases of improvement in delirium
`were seen, 3 cases of greatly improved ambition were
`observed, 3 cases of improved loitering were observed.
`Also, among the Alzheimer’s dementia patients we
`observed 1 case each of improved ambition, human
`relationships, and manic states, respectively, for a total
`of 3 observed improvements. The Unchanging
`Administration Group did not show any change in
`symptoms in this same period, and all cases were
`evaluated to have no change.
`[ 0024 ] Embodiment 2. Test to measure improvement of
`loss of intellectual capacity.
`
`The calculation skills, judgment, and higher functions of
`the same test group as test 1 were evaluated. This test
`was a simple evaluation of intellectual abilities. Also, a
`course correction and pathfinding test was administered
`as a simple measure of motor control. The test was
`administered twice, once before administration of DHA
`and once 6 months after the administration of DHA. The
`
`results were statistically aggregated. The results are
`shown in Table 2.
`
`[ 0025 ]
`[Table 2]
`
`Table 2. Level of Improvement of Intellectual Abilities
`— DHA Admin Group
`Unchanged Group
`Intellectual Ability
`Preadmin (at
`6 months post
`Pre-admin
`6 months
`test start time)
`— admin
`ost - admin
`6.2 +- 3.3
`6.9 --- 3.0
`.
`- 3.3
`
`Total Judgment Total
`
`Calculation Abilities
`
`Hiher Function Total
`
`.6 -
`.1 -
`
`
`
`6.0---2.9
`
`3.4 --- 2.4
`
`3.6---3.3
`
`
`
`
`
`[ 0026 ] Note that in both the motor and IQ tests,
`
`improvements were seen after the administration of
`DHA.
`
`Continued from the front page
`
`Miyakawa Fumio
`(72) Inventor
`Kanagawa-ken, Sumohara-shi, Nandai l — 2 — 12
`
`Muramatsu Ei
`(72) Inventor
`Tokyo-to, Hino-shi, Nishi Hirayama 5 — 27 — 10
`
`000004
`
`AKER877ITC00804521
`
`000004
`
`