Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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; 20 Background of the In~ention
21 This invention relates to therapeutic compositions
22 containing certain selenium compounds. These therapeutic
23 compositions have been found to exhibit surprising and unexpected
24 prope~ties in mammalian hosts. More particularly, the selenium
compounds in accordance with the present in~ention are water
26 soluble organic or inorganic compounds containing selenium in a
27 form capable of being absorbed by the body tissue to be treated.
28 Preferably, the compounds are salts containing selenium in the
29 form of the selenite or selenate anions. In the practice of the
present inventioll, the therapeutic compositions are formulated
31 so that ~aid selenium compounds are present in certain specific
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1 l amounts and concentrations so that they are non-toxic yet
2 ~I therapeutically active.
3 I Selenium is one of numerous elements found in trace
4 i amounts in many foods. The seleni~m is present in many
5 il chemicals and often in very complex forms. Many technical
I studies have been carried out concerning its biological effects
7 1 although tl~e majority of the work has dealt with those adverse
effects which occur by ingesting more than trace amounts of
9 selenium-containing compounds.
Research studies to date have indicated that selenium
11 doea hav~ beneficial physiological effects on mammals. For
; 12 examp~e, it is known that selenium, when ingested, reduces
13 the rat~ of oxidative damage caused by chemicals, such as, for
14 example, ozone in smog, by entering the membranes of the body's
cells and protec~ing the contents of the cells from reacting
16 with oxygen in a manner that tamages the cells. It has also
17 been reported that selenium may be beneficial in the trea~ment
18 l of heart disease by reducing or decreasing coronary vascular
19 resistance in d~gs. Additional studie5 have Al80 shown some
beneficial effects of 8elenium in cancer therapy. In combination
21 with Vitamin E, selenium has been reported to have a beneficial
22 effect in relief of arthritis and tendonitis.
23 ¦ On the other hand, there has been considerable
24 reluctance to prescribe usages of selenium because of its
apparent toxic effects when present in large dosages. While
26 numerous medical and governmental reports have found selenium
to ha~e general toxic properties in adult mammals, there i5 no
28 consensus as to specific toxicity levels nor toxicity effects.
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It is known r however, that deleterious effects on
2 1I the heart, lungs, liver and kidneys do occur, in addition to
3 ¦1 adverse e~fects on other body systems in mammals, both humans
4 I and animals, in cases where selenium is ingested. But the
particular amounts ingested which cause such effects vary
6 ~ widely depending upon the form of the ingested seleniu~, and
7 ¦ the presence of other materials in the diet of the host. For
~ ! example, protein is reported to afford some protection against
-; the toxic effects of selenium.
It is therefore surprising that in accordance with
i 11 the pre8ent invention it has been discovered that pharmaceuti- I
12 cally safe compositions have been formulated which have
; 13 unexpected therapeutic and physiological properties and benefits ¦
14 which enable it to be easily formulated and administered to
! lS mammals, including humans. Also provided by this invention I -
16 are methods of treating mammals, including humans, to reduce
~7 the severity from and to improve recovery from certain
18 physically induced injurie9 to ti8sue caused by physical
l9 effect8 or irritating stimuli such as surgical operations,
laceratio~s and ~urns including electrical, sun and thermal
21 burns, etc.
22
23 Summary of the Invention
24 In accordance with the present invention, there are
25 ¦ ¦ provided therapeutic compositions for treating mammals, including
26 1 humans, comprising a therapeutically effective but non-toxic
i 27 ¦ amount of a water 901uble organic or inorganic selenium compound
28 combined with a pharmaceutically acceptable carrier or vehicle
29 therefor. In general, such compositions comprise about 0.05 mg
to about 1.0 mg and prefer~bly 0.5 to 1.0 mg of elemental .
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1 1~ selenium by weight, based on the total weight of the composition,-¦
2 1 in the finished dosage form.
3 ¦ The selenium compound is preferably a water soluble
4 ¦ organic or inorganic selenite or selenate such as i~lkali
5 ¦ metal selenites or selenates. The composition may be
6 ~ fomulated for oral, injectable, topical or suppository
7 ¦ administration. For example, tablets, capsules, solutions,
8 ¦ creams and the like may be made where the selenium compound
9 ¦ is dispersed substantially homogeneously throughout a suitable ¦ ;
10 ¦ pharmaceutically acceptable carrier or vehicle in such finished
11 ¦ dosage form.
12
13 ¦ Description of the Preferred Embodiments
; I Compositions in accordance with the present invention
which contain certain selenium compounds in therapeutically
16 effective but non-toxic dosages can be administered to mammals
17 for the purpose o~ reducing the severity from and improving
18 the recovery from physically induced tamage to the host's
19 tissue. By phys~.cally induced damage is meant vari~us types
of damage to the tissue of a mammal including, for example, L
21 surgical incisions, lacerations, burns, etc. Accompanying such
22 damage are the likelihood of infection, edema, ecchymosis
23 and other in~la~atory responses. It has been found that
24 where the therapeutic compositions of the present invention
are administered prior to such physically induced damage to
26 ¦ tissue, such as prior to surgery, an observable improvement
27 ¦ in the patient's healing of the tissue and a reduced degree of
28 ¦ infection, edema, ecchymosis and other inflammatory responses
29 1 are noted.
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; 1 It has also been found that the therapeutic
2 composition of the present invention can be administered subse-
3 quent to the physically induced damage to tissue and improve
4 the recovery of the tissue and affected areas. For example,
5 the compositions of the present invention may be applied
6 topically to the specifically affected areas of the skin to
7 reduce scarring, etc.
8 It is also intended that physically induced damage
9 in accordance with the present invention should include
damage due to burns. It has been found thiat lesions and scars
11 to the skin due to burning and other tissue damage is reduced
12 and in some cases eliminated and that recovery is accelerated
13 by use of the composition of the present invention.
14 The anti-inflammatory properties of the selenium
! 15 ¦ compositions of this invention provide useful advantages
16 ¦ when employed alone or with other materials utilized, for
17 ¦ example, in pre-operative or post-operative surgical
18 ¦ procedures. For example, various compounds such as steroids
19 ¦ have been allege~ to possess anti-inflammatory properties.
20 ¦ Included among these are, for example, cortisone and hydro-
21 ¦ cortisone.
22 ~ The selenium compositions of this invention used
23 alone exhibit effective anti-inflammatory properties without
24 the detrimental side effects of some known materials which
exhibit anti-inflammatory properties. The selenium compounds
26 of the present invention may be combined with materials having
27 compatible properties to form compositions exhibiting the
28 beneficial effects of the selenium compounds, as well as
29 enhan d beneficial effects of these other materials.
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1 The primary active ingredient in the therapeutic
2 compositions of the present invention is the selenium compounds.
3 It is to be noted that selenium occurs in a number varying
4 valence forms. For example, selenium compounds in which
the selenium has a +4 valence, usually as the selenite and
6 selenate ions, may be utilized in the compositions of this
7 invention. Among the selenite and selenate forms, the preferred
8 compounds utilized in the compositions of this invention are
9 the water soluble alkali metal salts thereof, and particularly,
the sodium and potassium salts, that is, sodium and potassium
11 selenite and selenate. On the other hand, organic compounds of
12 selenium may also be uti.~ized in the compositions of this
13 invention. For example, selenium compounds of cystine and
14 methionine, as well as the aliphatic mono- and di-selenodi-
carboxylic acids having about 7 to 11 carbons in the carbon
16 chain may be used. Particularly useful acids of this group
17 include monoseleno-ll,ll'~di'n-undecanoic acid, diseleno-4,4'-
18 di-n-valeric aci~ and diseleno-ll,ll'-di-n-undecanamide. It
1~ is to be understood, however, that the particular organ~c forms
of selenium compounds set forth herein are not to be considered
21 limitati~e. Other organic selenium compounds which exhibit
22 the desired actici.t.y and are compatible and non-toxic can
23 be used in the pr~ctice of this invention.
24 It is a critical aspect o this invention that the
selenium in the form present in the composition be capable of
26 being absorbed by the tissue of the body to be treated. It is
27 noted that water insoluble selenium compounds are not generally
28 ~ ¦ absor ~d on this ] evel.
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The compositions of this invention can be made by
2 ¦I mixing a suitably appropriate carrier and the sel~nium compound
3 1~ together and agitating the mixture until homogeneity is attained.
4 ¦~ The concentration of the seleni~m compound to be
5 ~ present in a particular composition will depend upon the means ';
¦ of administration and nature of the composition. For exampLe,
7 ¦ compositions for topical administration should have generally
8 1 a lower concentration of elemental selenium than compositions
¦ for other types of administration.
10 1 The selenium compound can be present in such an
11 ¦ amount 80 that the elemental selenium concentration of the
12 1 therapeutic composition is in the order of from about 0.005 to
13 ¦ about 2 mg per gram of the total weight of the composition.
14 1 The concentration, of course, depends upon the therapeutic
i 15 l¦ activity desired and toxicity maximum levels.
16 ¦ As the daily dosage range is of the order of about
17 0.05 to 1.0 mg and preferably 0.5 to about 1.0 elemental
18 selenium, it i9 convenient as a practical matter to formulate
19 the composition so that about 0.5 mg to about 1.0 mg of
; 20 elemental selenillm is present in a given dosage amoun~ of the
21 composition.
22 The compositions of the present invention are quite
23 stable and can bc pre-mixed in the form of subsequent
24 administration. ~rt recognized techniques for packaging,
2S storing and preparing medicinal compositions for administration ¦
26 are generally applicable to these compositions.
27 ¦ As noted above, the therapeutic compositions in
28 1~ accordance with the present invention may be made in various
29 ¦I physical forms for well known methods of administration. For
30 ,1 example, the composition can be in a suitable form for injectable
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1 ¦ topical, suppository and oral administration. The choice of ¦ -
2 the particular carrier or vehicle and other additives present
3 li will depend upon the form desired. Said compositions may
4 l¦ also be combined with other materials such as cleansing and
5 ¦l antiseptic-type a~,ents.
6 ¦~ In carrying out the practice of this invention, a
7 1 wide variety of carriers or vehicles for the selenium can be
8 1 utilized and the terminology "pharmaceutically acceptable
9 carrier or vehicle" as employed throughout this specification
and in the appended claims is to be understood to include any
11 known carriers or vehicles generally employed in the pharmaceuti-
12 cal field including inert and active carriers or vehicles. The
13 vehicles or carriers should not detrimentally affect any of
14 the active ingredients of the composition.
15 1 Exemplary inert carriers or vehicles include: sugars
1~ ¦ and milk sugars, such as lactose; liquids, such as water,
17 ¦ isotonic aqueous solutions, saline solutions and alcohol; and
18 I inert powders, creams, salves, ointments, cleansing and
19 I antisep~ic agen~s and the like.
20 I Pharm~ceutically active carriers or vehicles may
21 also be used. Tllese may include physiologically active powders,
22 liquids, salves, creams and ointments as weLl as materials such
23 as vitamins, 8 tcloids including cortisone and hydrocortisone.
24 Other materials include proteolytic enzymes, such as those
obtained from the pineapple plant and sold under the trade name
26 I of Ananase by William H. Rorer, Inc. of Fort Washington, Pa.,
27 ¦¦ USA, proteolytic enzymes obtained from the papaya plant and
28 1l sold under the trade name of Papase by Warner/Chilcott, Division
29 ~ of Warner-Lambert Company of Morris Plains, New Jersey, USA,
30 1! and others, such as animal pancreas extracts which contain
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1 ! trypsin and chymotrypsin, one form of such extract being sold
2 ¦ under the trade name of Chymoral by Armour Pharmaceutical Co. of
3 ¦ Phoenix, Arixona, USA.
4 ¦~ For oral administration, the therapeutic composition
5 ~l of the present invention can be prepared in dosage form as
6 ¦¦ capsules, tablets, powders, syrups, oral solutions and the like.
: 7 1I These orally administrable compositions may contain such addi-
¦ tives as diluents, fillers, lubricants and glidants. Where they
9 ¦ are in the form of a liquid, they should be suitably prepared
I so that the ingredients including the liquid pharmaceutical
11 carrier are bland to the gastric mucosa.
12 In the case of the injectable form of the composition,
13 ¦ the therapeutic selenium compound may be dissolved in distilled
14 or sterilized water to form a parenteral preparation, or it can
I be mixed with intravenous infusions such as glucose or saline.
16In accordance with this invention, selenium can be
17 utilized in compositions suitable for topical, dermatological
18 applications. In this regart, the selenium compounds can be used
19 for skin treatmcnts and maintenance in dermatological creams,
; salves, and the like. Such compositions can be effective in
21 treating skin irritations, certain rashes, dermatit~s, eczema o~
22 and pruritus. Such compositions also have properties making them
23 useful in reducing the rate of cell aging due to exposure to
u 24 light and oxygen which generally results in an oxidizing condi-
tion that weakens the cell membranes, thus causing the cells to
26 deform. In this regard, it is to be noted that the number o
27 damaged cells generally increases rapidly with the time of
28 exposure to light and oxygen. However, the use of dermatological
29 preparations containing selenium in accordance with this inven-
~0 t tion dramatically interrupts or stops such damaging effects.
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1 The topical forms of the compositions of the present
2 invention are also particularly effective in improving and
3 accelerating the healing of tissue damaged by burns, which
4 includes burns caused by the sun, heat, electricity,
¦ radioactive exposure and chemicals. .
6 ¦ It is also to be noted that selenium compositions
7 I in accordance with the invention prevent distortion or adverse
8 ¦ bio-chemical effects in cells which are subjected to ultraviolet
9 ¦ light which greatly damages the membrane of such cells.
10 ¦ T~e composition of the present invention may be
11 admin~stered as eye drops in the form of a very dilute isotonic
12 aqueous solution, that is, from about 0.1 mg to 0.5 mg of
13 elemental selenium per cc solution and properly buffered to
14 substantially neutral pH of about 6-7. Such eye drop solutions
1 15 are useful in relieving eye irritation and redness caused by
16 dust, smoke, smog, wind and sun glare, swimming, strain due to
17 readin~ and television viewing or in the problems encountered
18 1 in adapting to thc utilization of contact lenses. A daily dosage
of such an eye drop solution would be in the order of 1/20 to
20 1 1/5 cc.
21 ¦ It i9 to be understood that the particular carriers
22 ¦ or vehicles set out above are illustrative only and other known
23 ¦ pharmaceu~ically acceptable materials can be utilized in the
24 compositions o this invention so long as they do not react
25 with the seleniu~ and other active ingredients to destroy the ,
26 identity thereo~. Moreover, the particular carrier or vehicle
27 chosen for use will depend upon the form of the composition
28 needed for the particular method o~ administration and the
29 host to receive the composition.
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1 ¦ In those cases where the composition contains more
2 I tl~an about 1.0 mg by weight, the composition may be employed
3 in the form of divided dosages when being administered whether
4 it be in the form of a tablet, a capsule or a liquid solution.
I Moreover, a particular dosage in this respect can be administered
6 several times a day so long as the total amount of selenium
7 compound does not exceed the generally accepted maximum of
8 about 1 0 mg per day.
9 In some instances, the composition of this invention
can be made by simply mixing the selenium compound in proper
11 proportion with an appropriate carrier. For example, in
12 preparing tablets, an alkali metal selenite or selenate salt
13 in its dry form may be mechanically mixed with a powdered
14 carrier or vehicle and shaped or pressed into tablets or
lS encapsulated by known art recognized techniques. On the other
16 hand, if desirable, such salts can be dissolved in water and
17 then mixed with A powdered carrier and shaped or pressed into
18 tablets.
19 As an alternative, liquid compositions can be prepared
simply by disso].ving the selenium compounds in water and using
21 the composition in tllat form with recognized additives for
22 either external or oral application. The materials as mixed
23 shoult contain at least a 0.05 mg dosage of selenium to achieve
24 most therapeutic benefits and may contain up to an amount
conveniently combinable with the carrier to provide a daily
26 dosage of selenium in a range of from about .05 mg to about
27 1.0 mg ? and preferably from about 0.5 mg to about 1.0 mg.
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1 ¦~ While t~le stated range is generally a beneficially
2 ~ useful amount of selenium in accordance with this invention,
¦it is also to be understood that this range is normally the
4 amount given to an adult mammalian individual. However,
5 dependent upon the weight and age of an adult mammalian host,
6 the amount ingested by such a host may be adjusted accordingly
within the stated range or somewhat outside the minimum and
8 maximum thereof. The total overall amount to be ingested per
9 day by a relatively small or young individual, or example,
is preferably near the lower end of the range and for
11 larger or older individuala, toward or in the area of the
12 upper end of the stated range. A general range for daily
13 treatment dosages, again based upon the purpose of treatment
14 and other factors of the individual, would be in the range
0.005 - 0.02 mg per kg weight of the host.
16 In using the selenium compositions of this invention
17 with the view to obtaining the pre-operative and post-operati~e
18 benefits thereof, the compositions may simply be administered
19 orally to an adult patient or host in divided doseY for
several days, e.g., ~rom 1-7 days,preceding surgery in the
21 stated concentrations or for several days, e.g., from 1-7 days
22 following tlle sur~lcal procedure or other trauma. For example,
23 an aqueous .solutiotl of sodium selenate or sodium selenite
24 can be made in a concentration to provide 5.0 mg of selenium
and then sub-divided by dilution to provide an equivalent amount
26 of selenium of 0.5 to 1 mg and administered in daily amounts
27 orally or otherwise for a period of 1-5 days preceding and
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1 ll following surgery. On the other hand, the selenium may also be
2 ~ administered orally, intraveneously or subcutaneously, for
3 !¦ example, by dissolving sodium selenate or sodium selenite in
4 ¦! water in an amount such that one drop of the solution yields
1 0.33 mg of selenium. The concentration may be based upon one
6 ¦ drop of the solution~being equal to l/20 of a cc. More dilute
7 and concentrated solutions may also be used.
8 In accordance with the present invention, the
9 effectiveness of selenium is generally enhanced by administering
¦ the same simultaneously with other physiologically active
11 ¦ materials. For example, compositions in accordance with this
12 invention can comprise small amounts of selenium combined with
13 Vitamin E, wherein the Vitamin E is present in the range from
14 about 10 I.U. to about 1000 I.U., and preferably from about 200
I.U. to about 800 I.U. The combination permits advantageous
16 beneficial effects due to the presence of selenium with the
17 vitamin, it being understood that in use further appropriate
18 dilution takes place so that the daily amount of elemental
1~ ¦ selenium atministered toes not exceed 1.0 mg.
The selenium can also be combined with ascorbic
21 acid, i.e., Vitamin C and utilized in the pre-treatment of
22 patients undergoing elective surgery. Due to the fact that
23 some selenium does form a precipitate with the Vitamin C, an
24 appropriate method of administration should be used to minimize
this precipitation effect.
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1 l¦ The present invention presents many advantage5 both
2 I in its therapeutic effects and in the ability to formulate
3 I administrable compositions. When ingested, selenium is
4 ~ distributed to all of the cells in the body and is stored non-
I selectively but not uniformly, as is the case with several
6 11 other elements such as chromium, iodine, and calcium.
7 Compositions of this invention are relatively simple
8 I to prepare. The water soluble sodium and potassium salts of
9 I selenium are readily available and are easily incorporated
into a suitable pharmaceutical carrier or vehicle without the
11 neet for extraordillary and elaborate manu~acturing equipment.
12 Moreover, if desirable, the selenium salts can be distributed
13 in a suitable carrier and stored for long periods of time
14 without loss of effectiveness. On the other hand, if desired,
! 15 the salts can be marketed separately and simply mixed or com-
16 pounded with a carrier just prior to use. Numerous other
17 ¦ advantages of this invention will be readily apparent to those
18 ¦ skilled in the art.
1~ Numerou9 ulodifications oE this invention may be made
without departin~ from the spirit and scope thereof. Accordingly,
21 it is to be understood that this invention is not to be
22 limited to the illustrative embodiments set forth herein.
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1 'I EXAMPLE 1
2 ! This example is presented to illustrate the tolerance
j and effect of compositions of the present invention as adminis-
tered to humans. The patient chosen for this example was
1 22 years old. Some four years prior to receiving the treatment
6 ¦ in accordance with the present invention, he had undergone a
7 ¦ rhinoplasty surgery which resulted in severe and alarming
8 1 post-operative ecchymosis, edema and blood red eyes. The
9 rhinoplasty surgical procedure involved the fracture of the
patient's nose and associated trauma associated with the
11 surrounding tissues. This prior treatment and recovery of the
12 patient acts as a control to the instant exam~le.
13 Four years after the aforementioned rhinoplasty
14 ~ surgery and after some three and a half years following
15 ~¦ complete recovery, the patient received the treatment in accord-
16 ¦ ance with the present invention which contained 0.65 mg of
17 I selenium. This oral dosage was prepared as follows:
18 ¦ One ounc~ of sodiu~ selenite as obtained
14 from City Chemical Corp., of New York,
21 Mew York, was added to ordinary tap water
to yield a concentration of 28~35 mg of
22 sodium selenite (~a2SeO3) to 1 cc of
23 water. This is equivalent to 13.0 mg
24 of elemental selenium per cc of water.
The foregoing solution was ingested in an amount daily to yield
26 a daily dosage of 0.65 mg per day. The daily dosage was
27 ¦ continued for a period of seven days. On the evening of the
28 seventh day of treatment, the patient was involved in an
¦ automobile acci~ent in which he suffered head, nose and facial
30 ! iRjuries. This included a fracture of his nose and associated
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1 ¦¦ trauma to the surrounding tissue. The patient received
2 ,11 emergency hospital treatment including examination and
3 treatment by a plastic surgeon. During the course of the
4 patient's recovery, there was no observed ecchymosis or edema
5 ¦ of the nose, eyes or face, although trauma had been sustained
6 ¦ as a result of the accident. `~'
8 I E~AMPLE 2
g 1l This example illustrates the effect of orally ¦
ingesting the therapeutic composition of the present invention
11 on the irritation of the eyes of a human patient. The patient
12 was a wearer of contact lenses and for many years suffered
13 ¦ regular inflammation and irritation due to the wearing o
14 1 contact lenses. The patient received by oral ingestion the
15 1I therapeutic composition prepared in accordance with Example 1
16 ¦¦ 'in an amount equivalent to a daily dosage of 0.5 mg of selenium.
17 ! A~ter a period of S days the redness and inflammation that was
18 I normal,ly present in his ~yes subsided and discontinued.
19 After his eyes reached an optimum improvement, he discontinued
the ingestion of the therapeutic composition for a period of
21 seven days. Ater those seven days, the patient's eyes became
22 'inflamed, red alld irritated to the same extent as existed
23 prior to the original treatment with the therapeutic composition
24 ¦ as noted above. A subsequent resumption in the ingestion of
25 ¦ the therapeutic compositlon again improved the patient's eyes
26 1 as during the prior treatment period. No side effects from
27 this treatment have been observed. ¦
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