`
`0610587‘
`
`volume 52, number 10
`
`Sciences
`
`Review Article__
`
`Use of Nonaqueous Solvents in Parenteral Products
`
`By A. J. SPIEGEL and M. M. NOSEWORTHY
`
`THE PRACTICE OF incorporating naturally oc-
`curring nonaqueous solvents such as fixed
`oils and glycerin in pharmaceuticals has been
`common for many years. Water is always the
`solvent of choice. However, when it
`is not
`possible for physical or chemical reasons (such as
`limited solubility and hydrolytic reactions) to
`use a wholly aqueous system, nonaqueous sol-
`vents aid the formulator in developing stable,
`convenient parenteral dosage forms. A paren-
`teral solution avoids the disadvantages inherent
`in suspensions, such as nonuniform dosage, cak-
`ing, and possible slow release of the medicament
`when it is not desired.
`
`A formulator encounters many problems once
`he determines that an aqueous system is un-
`satisfactory. The chosen solvent must be non-
`toxic, nonirritating, and nonsensitizing.
`It also
`must exert no pharmacologic activity of its own,
`nor adversely aflect the action of the medica-
`ment. There are reported instances in which a
`solvent potentiated the activity of the medica-
`ment necessitating a change of dosage level.
`This will be discussed in greater detail later in
`this review.
`
`jection, and the solvent must remain fluid over a
`fairly wide temperature range.
`It is advantage-
`ous if the solvent has a sufliciently high boiling
`point
`to allow heat sterilization. Additional
`considerations are water and body fluid misci-
`bility,
`the degree of flammability, availability,
`source of supply, and constant purity.
`Obviously, no such individual solvent presently
`exists. Thus,
`the selection of a nonaqueous
`solvent for a parenteral vehicle is a compromise
`among the many influencing factors. The ad-
`vent of modern chemical technology has pro-
`duced many new synthetic solvents in addition to
`the naturally occurring ones.
`This review presents the toxicity, chemical and
`physical properties, and applications of some of
`the more commonly used nonaqueous solvents,
`as well as some specialized and rarely used sol-
`vents in pharmaceutical formulations.
`
`FIXED OILS
`
`In addition to being pharmacologically accept-
`able, the chemical and physical properties of the
`solvent must be taken into account. Thus, the
`ideal solvent should not be aflected by acids or
`alkalies and it should be generally stable under
`normal conditions of pharmaceutical use. The
`viscosity must be such as to allow for ease of in-
`Received from the Pharmaceutical Research and Develop-
`ment Department, Chas. Pfizer & Co., Inc., Brooklyn, N. _Y.
`Presented in part at the Fourth Annual National Industrial
`une
`.
`gharnligggutical Research Conference, Land O'Lakes, Wis.,
`917
`
`The U.S.P. (1) recognizes the use of fixed oils as
`parenteral vehicles. Fixed oils are mainly mix-
`tures of esters of unsaturated fatty acids which
`are fluid at 20°. The fluidity is generally due to
`the presence of the oleic acid esters of glycerin.
`The most commonly used fixed oils are corn oil,
`cottonseed oil, peanut oil, and sesame oil (2).
`Castor oil and olive oil have been used occasion-
`
`ally. While the toxicities of vegetable oils are
`relatively low, some patients exhibit allergic re-
`actions to specific vegetable oils. Therefore,
`when such oils are used as vehicles, the label must
`state the specific oil contained in the product.
`Fixed oils have been known to cause undesirable
`
`|nnoPharma Exhibit 1072.0001
`
`
`
`918
`
`local tissue reactions, such as cysts, foreign-body
`granulomas and, occasionally, nerve injury.
`The requirements for fixed oils to be used in
`parenteral products are specified in the U.S.P. (1).
`The use of fixed oils is limited because of the low
`
`Since
`solubility of most drugs in these solvents.
`these oils are not miscible with water, dissolved
`drugs may exhibit a sustained-release effect with
`a possible diminution of absorption. Aqueous
`insolubility also precludes the use of fixed oils in
`unemulsified intravenous products.
`Cottonseed oil has been used in intravenous fat
`
`emulsions administered to surgical patients as
`reported by Lehr and co-workers (3) and a com-
`merical product is available.
`Drugs which are incorporated in oils are mainly
`the steroid hormones, dimercaprol, calciferol,
`and menadione.
`Since fixed oils contain un-
`
`saturated fatty acids, oxidative changes take
`place which may necessitate the use of oil soluble
`antioxidants such as propyl gallate, butylated
`hydroxyanisole, butylated hydroxytoluene, and
`tocopherols.
`(4)
`(1) and N.F.
`A list of the official U.S.P.
`parenteral solutions using fixed oils as solvents
`is given in Table I.
`
`TABLE I.-—OFFICIAL INJECTIONS IN OIL
`
`Desoxycorticosterone acetate U.S.P.
`Dimercaprol U.S.P.
`Estradiol benzoate U.S.P.
`Estradiol cyclopentylpropionate N.F.
`Estradiol dipropionate U.S.P.
`Estrone U.S.P.
`Progesterone U.S.P.
`Testosterone propionate U.S.P.
`Diethylstilbestrol dipropionate N.F.
`Menadione N.F.
`
`A typical intramuscular formula for a testos-
`terone propionate oil solution, 50 mg./ml.,
`is
`(5)
`
`Testosterone propionate
`Benzyl alcohol
`Sesame oil
`
`Gm./1000 ml.
`50.0
`21 .0
`869.0
`
`Since sesame oil becomes turbid on cooling, a
`“winterized” or treated oil should be used, so
`that the oil remains clear when cooled to 5°.
`
`ETHYL OLEATE
`
`recognizes
`The “British Pharmacopoeia" (6)
`ethyl oleate as an alternative vehicle in injections
`of deoxycortone acetate, estradiol monobenzoate,
`progesterone, and testosterone propionate.
`It is a yellowish oily liquid which is insoluble in
`water a11d miscible with alcohol, ether, and fixed
`oils.
`It has properties similar to fixed oils, ex-
`
`Journal of Pharmaceutical Sciences
`
`cept that it is less viscous, is a superior solvent,
`and is more rapidly absorbed by the tissues (7).
`Unlike untreated sesame oil, ethyl oleate remains
`clear at 5°, but it has the disadvantage of dis-
`coloring on standing.
`There are indications of
`
`increased hormone
`
`activity when ethyl oleate is used in place
`of sesame oil as a parenteral hormone vehicle.
`Studies by Dekanski and Chapman (8) demon-
`strated improved intensity and duration of ac-
`tion of testosterone phenylpropionate and tes-
`tosterone propionate in ethyl oleate over that of
`the same androgens in sesame oil.
`
`ISOPROPYL MYRISTATE
`
`The use of isopropyl myristate as a vehicle for
`parenteral
`injections has been reported by
`Platcow and Voss (9).
`It is an oil miscible, water
`immiscible,
`chemically stable substance, not
`susceptible to rancidity and having a specific
`gravity of 0.852 (10).
`It consists mainly of
`isopropyl myristate and a small amount of
`isopropyl esters of other saturated fatty acids.
`Acute toxicity studies indicate a very low order
`of toxicity, but attempts to establish an LD5o in
`mice failed when dosages equivalent
`to 100
`ml. /Kg. did not afiect the test animals.
`Isopropyl
`myristate shows a very low degree of irritability
`and exhibits no sensitizing properties in rabbits
`and guinea pigs following topical and parenteral
`administration.
`In
`experiments
`on
`ovariec-
`tomized rats it compared favorably with sesame
`oil as a repository vehicle for estrogens (9). The
`external pharmaceutical use has been evaluated
`by Donovan, et al.
`( 11), who found it a useful
`intermediate solvent
`for
`the incorporation of
`phenol, cocaine, resorcinol, and salicylic acid into
`liquid petrolatum.
`
`BENZYL BENZOATE
`
`Benzyl benzoate (12) is a colorless, oily liquid
`with a pleasant aromatic odor.
`It has a specific
`gravity of 1.118, boils at 323°, and is insoluble
`in water or glycerin, but is miscible with alcohol,
`chloroform, ether, and fixed oils.
`Its structural
`formula is
`
`/
`
`\
`
`COOCH2
`
`Benzyl benzoate has found some use as a co-
`solvent in oleaginous injectables such as dimer-
`caprol injection, and in commercial preparations
`of hydroxyprogesterone benzoate where it is pres-
`ent in concentrations of 30% for the 125-mg.
`product in sesame oil, and 46% for the 250-mg.
`
`|nnoPharma Exhibit 1072.0002
`
`
`
`Val. 52, No. 10, October 1963
`
`919
`
`product in castor oil. The formula for the in-
`jection of dimercaprol B.P. (1958) is dimercaprol
`5.0 Gm., benzyl benzoate 9.6 ml., and peanut oil,
`to make 100 ml.
`
`capsules (23) and as a parenteral vehicle for a
`tetracycline preparation (24).
`
`GLYCEROL FORMAL
`
`Glycerol formal is a condensation product of
`glycerol and formaldehyde
`consisting of 3-
`hydroxymethyl-1,3-dioxolane (I)
`(25%) and 5-
`hydroxy-dioxane (II)
`(75%). The structural
`formulas are
`
`)cH2
`
`H,C—O
`I
`H?—O
`H2C—OH
`I
`
`O
`H2C
`I
`1
`+ HO—$H C|H2
`HzC
`O
`II
`
`It is a chemically stable, colorless, odorless liquid
`of low viscosity and is miscible with water in all
`proportions. Sanderson (25) reported that the
`LDmo for rats by intraperitoneal administration
`was 3000 mg. /Kg. and that the maximum symp-
`tomless dose was 1500 mg./Kg. The use of
`glycerol formal as a nontoxic solvent in toxicity
`testing has been suggested.
`It has been used
`as an industrial solvent and no toxic effects have
`
`been reported (25).
`
`GLYCOFUROL
`
`Glycofurol is a Hoffmann-LaRoche trade name
`for a tetrahydrofurfuryl alcohol polyethylene
`glycol ether containing an average of two ethyl-
`ene glycol units per molecule.
`It is a colorless
`liquid, miscible with water in all proportions and
`soluble in methanol, ethanol, n-propanol, and
`glycerin.
`It has a boiling point of 80—155° and a
`specific gravity of 1.078. The structure is (26)
`H2C
`CH2
`I
`I
`H2C
`HC—CH2(0CH2CH2),.OH
`\O/
`n~2
`
`Spiegelberg and co-workers (26) extensively studied
`the pharmacology of this material and reported
`on its use as a parenteral solvent.
`Irritating
`when administered undiluted, it is nontoxic and
`nonirritating when diluted with water. The
`intravenous LD5o in the mouse is 3.78 Gm. (3.5
`ml.)/Kg., and its tolerability equals that of
`propylene glycol. Acetylcholine chloride is re-
`ported to be stable in glycofurol solutions, while
`it is not stable in propylene glycol.
`
`DIMETHYLACETAMIDE
`
`Dimethylacetamide (DMA), also known as
`acetic acid dimethylamide and acetyldimethy1-
`amine, is an interesting solvent which warrants
`some discussion.
`It is a clear neutral
`liquid
`
`DIOXOLANES
`
`The dioxolanes represent a new and interesting
`group of synthetic solvents for pharmacists.
`These substances are the reaction products of
`glycerin with ketones in the presence of a de-
`hydrating agent (13). The least toxic member
`of
`the group is 2,2-dimethy1-1,3-dioxolane—4-
`methanol (14). This structural formula is
`
`‘i‘
`H—C—O
`
`H—C—O
`
`\ /
`C
`/ \
`
`CH:
`
`C
`
`Hz
`
`IC
`
`H20H
`
`iso-
`This compound [also known as Solketal,
`propylidene glycerol, and glycerol dimethylketal
`(l5)] is reported to be a nontoxic, nonirritating
`solvent, miscible with water, alcohol, esters,
`aliphatic and aromatic hydrocarbons, and vir-
`tually all other organic solvents.
`It is a water-
`white, practically odorless liquid of medium
`viscosity, stable on storage, and unaffected by
`alkalies.
`Its boiling point is 82—83°, and has a
`specific gravity of 1.064.
`It is, however, hydro-
`lyzed by strong aqueous acid solutions to acetone
`and glycerin (15-19).
`Berger (14) reported the dioxolanes (as a class)
`produce transient muscular relaxation and paral-
`ysis. These eflects were due to a depressant
`action on the central nervous system and not to a
`peripheral curare-like action. The mean para-
`lyzing dose, EDW, and the mean lethal dose, LD5o,
`for 2,2-dimethyl—l,3-dioxolane-4-methanol after
`intraperitoneal administration in mice was re-
`ported to be greater than 2.112 Gm./Kg. (16.0
`mM/Kg.).
`Teuber (20, 21) reported that the oral LD5o in
`mice is 4.0 to 7.2 Gm./Kg.
`(30-55 mM/Kg.).
`Dermatologic tests on rabbits produced no un-
`toward reactions after 3 weeks of application.
`Guinea pigs exposed to aerosol sprays for 1
`hour a day for 3 days exhibited no inflamma-
`tion of mucous membranes. Huber
`(22)
`re-
`ported on the use of antibiotic aerosol sprays
`utilizing this solvent as a carrier for penicillin
`and oxytetracycline.
`In this country, 2,2-dimethyl-1,3-dioxolane-4-
`methanol has been reported in the patent litera-
`ture as a water-miscible solvent
`in gelatin
`
`|nnoPharma Exhibit 10720003
`
`
`
`920
`
`having a boiling point of 165.5°, a specific gravity
`of 0.943, and a molecular weight of 87.12. The
`structural formula is
`
`CH;
`
`CHa—C—N
`ll \
`0
`
`CH,
`
`This solvent is miscible in all proportions with
`water and alcohol and very soluble in organic
`solvents and mineral oil (27).
`studied the acute
`Davis and Jenner
`(28)
`toxicities of dimethylacetamide, dimethy1form-
`amide (DMF), and propylene glycol after single
`doses were administered intraperitoneally to
`mice. A 50% solution of DMA was used;
`however, the toxicity results are for the DMA
`content of the solution. The DMF and propyl-
`ene glycol were administered undiluted. These
`results are as follows: the LD.-.0 for DMF was
`1122 mg./Kg., for DMA 3236 mg./Kg., and for
`propylene glycol 11,400 mg./Kg. The LD1oo
`for DMA is 5012 mg./Kg.
`Horn (29) investigated the chronic toxicity of
`DMA by dermal application in dogs at dosage
`levels of 0.1 to 4.0 mg./Kg. and by exposing both
`rats and dogs to an atmosphere containing DMA
`at concentrations of 40.0, 64.4, 102, and 195 p.p.m.
`All experiments were of 6-month duration unless
`obvious toxicity occurred. Liver damage oc-
`curred at all
`levels greater than 0.1 ml./Kg.
`dermally and 40 p.p.m. by inhalation.
`The patent literature mentions the use of a
`50% DMA solution as a vehicle for a preconsti-
`tuted oxytetracycline (30) solution and as a
`solvent in soft and hard gelatin capsules (31).
`Its use as an anti-inflammatory agent in topical
`formulations is also reported (32).
`Hammer, et al.
`(33), reported on a precon-
`stituted intramuscular solution of oxytetracycline
`which consisted of a solution of an ethanol-
`
`ammonium magnesium salt of oxytetracycline in
`50% N,N-dimethylacetamide. After testing in
`animals and humans, this formulation was found
`to be well tolerated and produced efiective anti-
`biotic serum levels. The stability was satis-
`factory for 2 years at room temperature.
`A 50% solution of DMA is used as a solvent
`for a 250—mg./ml. chloramphenicol intravenous
`formulation, but it must be diluted with normal
`saline or 5% dextrose before administration.
`A commercially available reserpine
`intra-
`muscular product contains 10% DMA as a co-
`solvent (34).
`DMA, when used as a drug solvent and ad-
`ministered to 15 patients with advanced malig-
`nancies produced hallucinations when given at
`
`Journal of Pharmaceutical Sciences
`
`levels above 400 mg./Kg. of body weight per day
`for 3 days or more (35). However, the normal
`parenteral level for DMA is equivalent to 30 mg./-
`Kg. per day. Thus, in normal use this hallucina-
`genic effect would not be expected.
`An oxytetracycline 50-mg./ml. formula (30)
`was reported to have been composed of oxytetra-
`cycline, 50 mg. ; magnesium chloride, hexahydrate
`1.7%; ethanolamine, 20% aqueous 1.5%; sodium
`formaldehyde sulfoxylate 0.2%;
`lidocaine 2%;
`and N,N-dimethylacetamide 50%, to make 1.00
`ml.
`
`N- ()3-HYDROXYETHYL) -LACTAMIDE
`
`also
`N - (/3 — Hydroxyethyl) - lactamide (36),
`known as lactic acid carboxamide, is a clear, color-
`less, syrupy liquid which is water miscible. The
`specific gravity of the pure compound is 1.192.
`It is used as a 50% solution and has the following
`formula: CH3CHOHCONHCH2CH2OH.
`This
`compound is the reaction product of methyl ace-
`tate and 2-aminoethanol. The acute subcutane-
`
`ous, LDso, toxicity (37) for a 50% w/v N-(B-
`hydroxyethyl)-lactamide solution is 15.8 Gm.
`lactamide/Kg. in mice and 16.1 Gm. lactamide/-
`Kg. in rats. This compound has been used in
`Europe as a solvent for a preconstituted oxytetra-
`cycline solution. Neumann (37) reported that
`this product was stable for several years and
`showed improved tissue tolerability.
`Dimmling (38) has also reported on the use of
`N-()3-hydroxyethyl)-lactamide as a solvent for
`oxytetracycline. After 24 hours, a detectable
`serum level was found after a single dose of 250
`mg. in ten healthy persons. Following a second
`injection of 250 mg. after an interval of 24 hours,
`the levels showed a cumulative increase. Further
`studies (39) on the serum concentrations con-
`firmed the previous findings.
`The results of Seeliger’s (40) investigation with
`oxytetracycline intramuscular in N-(B-hydroxy-
`ethyl)-lactamide solution in patients have con-
`firmed the previous values obtained in healthy
`individuals. A single injection of 250 mg. gave
`an effective serum concentration for over 24
`
`hours. Following repeated injections on consecu-
`tive days, marked cumulative effects were ob-
`served. The clinical efiect was in accordance
`
`with blood level determinations. Survey of local
`tolerability showed practically no pain in 93.7%
`of the 380 injections performed; slight and tolera-
`ble local reactions, which in no case persisted for
`more than 2 or 3 hours, were found in 6.3%.
`Hupe (41) reported that in 90 major surgical
`cases 250 mg. of oxytetracycline intramuscular in
`this solvent, once a day, was effective and well
`tolerated.
`
`|nnoPharma Exhibit 1072.0004
`
`
`
`Vol. 52, No. 10, October 1963
`
`The patent literature also refers to the use of
`N-(5-hydroxyethyl) -lactamide as a solvent for
`oxytetracycline injectables (30, 42). The use
`of other alkylol amides such as the amides of B-
`hydroxybutyric acid, succinic acid, adipic acid,
`tartaric acid, glycolic acid, and salicylic acid, was
`also mentioned (42). A typical formula for a
`250 mg. /3 ml. oxtyetracycline product is
`Gm./100 ml.
`9.62
`4.00
`0.20
`44.20
`50 . 00
`2 . 30
`
`Oxytetracycline hydrochloride
`Magnesium chloride-hexahydrate
`Sodium formaldehyde sulfoxylate
`Water, pyrogen-free
`N-(H-hydroxyethyl )-lactamide
`Monoethanolamine
`
`ETI-IYL LACTATE
`
`a-hydroxypropionate,
`ethyl
`lactate,
`Ethyl
`is a colorless liquid
`CH3CH(OH)COOCH2CH;,,
`with a specific gravity of 1.042 which is miscible
`with water and has a characteristic odor.
`In
`
`aqueous solution some decomposition takes place
`(43).
`Latven and Molitor (44) determined the acute
`toxicity of ethyl lactate in mice by subcutane-
`ous and intravenous administration, and their
`results are shown in Table II.
`
`TABLE II.—AcU'rE Toxrcrrv on Erma. LACTATE
`
`LDo LDu LDm
`
`Minimum Maximum
`Sympt. Nonsympt.
`Dose
`Dose
`
`Subcutaneous,
`ml./Kg.
`Intravenous,
`ml./Kg.
`
`2.0 2.5 3.0
`
`0.2 0.6 1.0
`
`1.0
`
`0.3
`
`0.8
`
`0.2
`
`Ethyl lactate was irritating on intradermal
`injection in guinea pigs and on application to the
`eyes of rabbits.
`Ethyl lactate (10-100%) solubilizes an esterone
`injection in castor oil to a concentration of 3.5
`to 6.5 mg./ml. (45). This product is stable at
`room temperature (46).
`It has been used as an in-
`dustrial solvent and no toxic efiects from its use
`
`have been recorded (47).
`
`ETHYL CARBONATE
`
`Ethyl carbonate, diethyl carbonate, CH;CH,-
`
`921
`
`OCOOCH-.»CH;, has also been used as a solvent for
`erythromycin, but there is a paucity of literature
`on its use and toxicity.
`It is a liquid immiscible
`with water but miscible with alcohol and ether
`
`and has a specific gravity of 0.975 and a boiling
`point of 126° (48). This compound has also been
`used as an industrial solvent with no reported
`toxic effects (49).
`POLYETHYLENE GLYCOLS
`
`The polyethylene glycols (PEGs), as the name
`implies, are polymers of ethylene oxide (50) with
`the general formula: H0CH2(CH20CH2),,CH2OH,
`where n represents the average number of ethyl-
`ene oxide groups. These polymeric products are
`designated by a number which represents the aver-
`age molecular weight (51). Polyethylene glycol
`200, 300, 400, and 600 are moderately viscous,
`colorless, somewhat hygroscopic liquids. They
`are less volatile than glycerin and do not hydro-
`lyze or deteriorate (52). They dissolve in water
`in all proportions to form clear solutions (51).
`Polyethylene glycol 1000, 1540, 4000, and 6000
`ire white waxy solids (Table III).
`For the purpose of this discussion, we will con-
`fine 'our comments to the liquid polyethylene
`glycols which are more likely to be used in
`parenteral products. The literature abounds
`with papers discussing and describing measure-
`ments of the toxicity of the various PEGs by
`oral or topical routes (50-58). However, there
`is a scarcity of material on the parenteral ad-
`ministration. PEG 300 and 400 are better
`described than the other two members of the
`
`liquid PEG series. Only the parenteral LD5o’s
`(as shown in Table IV) were found by the authors.
`Oral and dermal toxicity data are given in Tables
`V and VI.
`
`Subcutaneous dosages of PEG 400 up to 10 ml.
`(ten times the human dose) in rats caused no
`permanent damage. The reactions were de-
`scribed as “blanching of the skin and scab forma-
`tion in 48 hours.” The test results were reported
`to be the same as with propylene glycol. PEG
`300 and 400 do not elicit a foreign body reaction
`in animals (52).
`In dogs, the removal of PEG
`
`TABLE III.—'PHYSICAL PROPERTIES or POLYETI-IYLENE GLvcoLs (51)
`
`PEG
`200
`300
`400
`600
`1000
`1540
`4000
`6000
`
`Av. Mol. Wt.
`190-210
`285-315
`380-420
`570-630
`950-1050
`1300-1600
`3000-3700
`6000-7500
`
`Sp. Gr.,
`20° C.
`1.125
`1 . 125
`1.125
`.
`.
`.
`1.151
`1.151
`1.204
`.
`.
`.
`
`Freezing or
`Melting
`Range, ° C.
`Super Cools
`-15 to -8
`4 to
`8
`20 to 25
`37 to 40
`43 to 46
`53 to 56
`60 to 63
`
`Viscosity,
`Cps. at
`210° F.
`4.3
`5.8
`7.3
`10.5
`17.4
`25-32
`75-85
`700-900
`
`Comparative
`I-Iygroscopicity
`Glycerol = 100
`70
`60
`55
`40
`35
`30
`.
`.
`.
`
`|nnoPharma Exhibit 1072.0005
`
`
`
`922
`
`Journal of Pharmaceutical Sciences
`TABLE IV.-—PARENTERAL Toxrcrrv or POLYETHYLENE GLYCOLS
`
`PEG
`300
`300
`-L00
`
`Animal
`Female rat
`Rat
`Mouse
`
`Route
`i.v.
`i.p.
`i.p.
`
`Dose
`LD5o
`LDw
`LD5n
`
`Value, rug./Kg.
`7 , 979
`19 , 125
`4, 200
`
`Ref.
`52
`50
`5%)
`
`TABLE V.—ORA1. AND DERMZAL Toxrcrrv 01-‘
`POLYETHYLENE GLvcoLs IN MICE (60)
`L [)5o
`Sublet hal
`Sublethal
`Mouse,
`Dose
`Dose
`oral
`Mouse, oral
`Mouse. s.c.
`ml./Kg.
`ml./Kg.
`ml./Kg.
`38 . 3
`30 . 0
`6 . 5
`47.0
`16.0
`8.0
`
`LDmo
`Mouse,
`oral
`ml./Kg.
`60
`
`P EG
`200
`000
`
`injection is rapid, since the
`from the site of
`material difiuses freely into surrounding tissue.
`When PEG -100 was injected intravenously into
`humans, 77% was recovered in the first 12 hours.
`Intramuscular injections in rats of five to ten times
`the expected human dosage levels of PEG 300
`produced ischemic necrosis of the muscle fibers
`when the dose infiltrated a muscle bundle. The
`
`tissue response was one of mild chemical inflam-
`mation (50).
`Lee and Anderson (61) determined the toxicity
`of vancomycin in 50% PEG 200 and of PEG 200
`alone. Their results indicated that PEG 200
`
`produced no apparent toxic effects when given to
`dogs at 1.0 ml./Kg. per day for 80 days intra-
`muscularly, or of 0.5, 1.0, 2.5, and 5.0 ml./Kg. as
`single intravenous doses. Venous carbon dioxide
`content, blood nonprotein-nitrogen, and blood
`alkaline phosphatase were normal, no gross or
`microscopic
`abnormality was
`found in the
`kidneys, circulatory system, or other organs.
`A dosage form for intravenous use containing
`nitrofurantoin was marketed some years ago con-
`taining PEG 300.
`In a study by McCabe, et al.
`(62), it was found that daily administration of 240
`mg. of nitrofurantoin in PEG 300 to 30 patients
`caused severe metabolic acidosis and nephropathy
`in seven resulting in two deaths. These damag-
`ing effects were attributed to the PEG rather
`than nitrofurantoin and that dosage form was
`withdrawn from the market.
`
`It should be noted that drugs dissolved in the
`PEGS may well present a toxicity and drug level
`much different from those reported in aqueous
`solutions or suspensions (51 ).
`Swanson and co-workers (63) investigated the
`efiect on the activity and toxicity of sodium
`amobarbital and sodium secobarbital by the
`addition of 60 and 70%, respectively, of poly-
`ethylene glycol 200. Their findings indicated
`that the addition of PEG 200 showed approxi-
`mately the same potency and toxicity as aqueous
`solutions of
`these barbiturates.
`The median
`
`TABLE \'I.—ORAL Toxrcnv on POLYETHYLENE
`GLYCOLS IN RATS (51)
`No- Eflect Dose
`with Repeated
`Feedings, Rats
`Single Oral l.Dso
`Gm./Kg./Day
`Rats Gm./Kg.
`28.9 ml. (32.51 Gm.) 0.88 (2 yr.)
`31.7 ml. (35.66 Gm.) 5.4 (90 days)
`43.61111. (49.05 Gm.) 0.96 (2 yr.)
`38.1 ml.(-12.86 Gm.) 2.42 (90 days)
`
`Poly—
`ethylene
`Glycol
`200
`300
`400
`600
`
`anesthetic dose (ADW) by vein in rats was 75.0
`:i:3.5 mg./Kg. for sodium amobarbital and 39.0
`d:1.2 mg./Kg.
`for sodium secobarbital. The
`median lethal doses (LD5o) were approximately
`twice as large as the AD,r,n’s. This ratio of nearly
`2:1 is common to most barbiturates in use.
`It
`
`was also reported that subacute toxicity experi-
`ments show that both barbiturates in PEG 200
`
`changes.
`produced no obvious pathological
`When injected intramuscularly in rabbits the
`aqueous solutions of the two barbiturates pro-
`duced more irritation in tissues than solutions in
`PEG 2200.
`
`Bodin and Taub (6-1) investigated the stability
`of sodium pentobarbital in aqueous solutions con-
`taining 0 to 60% of polyethylene glycol 400.
`Their results indicated that the pH influences the
`concentration of polyethylene glycol 400 required
`for optimum stability. At a concentration of
`30% and at a pH of 10, aseptic formulation of a
`stable product is possible. The addition of 10%
`ethanol permits sterilization by autoclaving with-
`out discoloration.
`It is also possible to prepare
`formulations containing 60% of the glycol and
`10% ethanol at a pH as low as 8. These solutions
`are also stable to autoclaving.
`Linde (65) studied the extent to which a num-
`ber of sodium salts of 5,5—disubstituted barbitu-
`rates such as phenobarbital, barbital, aprobar-
`bital, amobarbital, and pentobarbital could be
`stabilized by propylene glycol, polyethylene
`glycol 400, glycerin, and alcohol. Both the
`glycols, as well as alcohol, showed the same sta-
`bilizing activity. Glycerin had considerably
`lower stabilizing properties. With glycols as
`stabilizers,
`the various barbiturate derivatives
`studied displayed great differences in stability.
`The concentration of the solvent added to the
`
`solution was found to be the factor governing the
`stabilizing effect. The stability increased as the
`concentration was increased. A concentration of
`
`|nnoPharma Exhibit 1072.0006
`
`
`
`Val. 52, No. 10, October 1963
`
`50% was the highest used. The author (65) also
`established that stability of barbiturates dissolved
`in pure propylene glycol and polyethylene glycol
`400 was very good, and that a lowering of pH in
`alcohol solutions decreases the rate of deteriora-
`tion.
`
`The use of 10% polyethylene glycol 300 as a
`solubilizing agent for a 2.5 mg./ml. injection of
`reserpine has been reported by Leyden, et al. (66).
`Commercial reserpine products containing 10-
`30% PEG 300, as well as 25% PEG 400, are
`available.
`
`Higuchi and Lach (67) reported that although
`pentobarbital and barbital have little or no
`tendency to complex with polyethylene glycols,
`phenobarbital forms stable and stoichiometric
`molecular compounds with these macromolecular
`substances. Analysis indicates that one pheno-
`barbital molecule is bound by two ethylene oxide
`units of the polyether chain. They have also
`shown that phenolic compounds are bound by the
`polyethers in the same manner, the higher molec-
`ular weight polymers exhibiting greater complex-
`ing tendency than those of lower degrees of poly-
`merization. Several organic
`acids,
`such as
`salicylic acid and p-hydroxybenzoic acid, are
`only weakly bound.
`An erythromyciu ethyl succinate intramuscular
`product in a PEG vehicle is available, as is a
`secobarbital parenteral product in a 50% PEG
`vehicle. The specific PEG used was not indicated
`in either case.
`
`GLYCERIN
`
`Glycerin (68) is a clear, viscous, high-boiling
`liquid, which is miscible with water and alcohol
`and is a good solvent for many compounds.
`It is
`hygroscopic and will absorb several
`times its
`weight of water under conditions of high humidity.
`Glycerin tends to supercool rather than crystal-
`lize at lower temperature;
`its aqueous solutions
`resist freezing.
`The toxicity (69) is low with oral administra-
`tion. No deleterious effects were observed in
`man with 110 Gm. of glycerin per day for 50
`days. Normal growth and reproduction occurred
`in rats with 41% of glycerin added to the food
`for 40 weeks, and in dogs with 35% added for 50
`weeks. Drill (70) reports the oral LD.-,0 in rats for
`undiluted glycerin to be 25 Gm./Kg. and the
`intravenous LD5o is 5 to 6 Gm./Kg.
`There appears to be some controversy regard-
`ing the use of glycerin in parenterals, as in-
`dicated by reports that
`its administration to
`animals has caused hemoglobinurea (71, 72),
`hypotension (73, 74) and central nervous dis-
`
`923
`
`turbances (74), and weight loss (75). Hanke (76)
`has given an excellent review of the physiologic
`action of glycerin.
`There are, however, references to its use in
`human parenteral
`therapy. No toxic effects
`were noted after the administration of very small
`amounts of glycerin by intra—arterial administra-
`tion in the treatment of elephantiasis (77).
`Sloviter
`(78, 79)
`reported that
`the intra-
`venous administration of solutions containing 5%
`glycerin to experimental animals and to man
`caused no toxic or other undesirable effects.
`
`Humans were given intravenously 50 Gm. of
`glycerin in a liter of solution which also con-
`tained 50 Gm. of glucose and 9.0 Gm. of sodium
`chloride. No disturbances of cardiorespiratory
`or central nervous system function occurred, and
`no
`significant
`hemolytic
`effects
`occurred.
`Sloviter (78, 79) further stated that the previously
`reported toxic effects of parenterally administered
`glycerin were not observed, and that there were
`indications that these toxic effects were due to the
`
`osmotic disturbances produced by the injection
`of solutions of high glycerin concentrations.
`In
`the dog, the rapid injection of a concentrated
`solution produced a transient drop in blood pres-
`sure which the author believed to be due to a
`
`It was also sug-
`peripheral vasodilating effect.
`gested that intravenously administered glycerol
`may be useful as a nutritional agent as well as for
`a solvent in preparations of drugs for intravenous
`administration (79).
`Large parenteral doses cause convulsant and
`paralytic symptoms through direct action on the
`central nervous system. The blood corpuscles
`are also laked, probably caused by an osmotic
`effect as previously mentioned. The glycerin re-
`mains for a time, unabsorbed, and in high concen-
`tration at the site of injection, and the corpuscles
`are probably laked during their passage through
`this area (69).
`Lachaux (80) states that aqueous solutions of
`up to 30% glycerin are well
`tolerated intra-
`muscularly. Absorption is good and there is rapid
`dilution by the body fluids.
`Latven and Molitor (44) determined the intra-
`venous and subcutaneous toxicity in white mice.
`Their results are shown in Table VII.
`
`TABLE VII.——AcU'rE Toxrcrrv or GLYCERIN
`
`LDn
`
`LD5o
`
`Min.
`Sympt.
`LDioo Dose
`
`Subcutaneous,
`ml./Kg.
`Intravenous,
`ml./Kg.
`
`8.0 10.0 12.0
`5.0
`6.0
`7.0
`
`8.()
`3.0
`
`Max.
`Non-
`Sympt.
`Dose
`
`7.0
`
`2.0
`
`|nnoPharma Exhibit 1072.000?
`
`
`
`924
`
`Krause and Cross (81) have found that the
`solubility of phenobarbital
`in alcohol was en-
`hanced by the addition of glycerin. The maxi-
`mum solubility of phenobarbital
`in alcohol-
`glycerin mixtures was reached at a level of 80%
`alcohol and 20% glycerin.
`Linde (65),
`in his work on sodium salts of
`barbiturates, found that glycerin has considerably
`lower
`stabilizing properties
`than propylene
`glycol, polyethylene glycol, and alcohol.
`Husa and Jatul (82) found that after heating a
`sodium phenobarbital solution in 50% glycerin
`for 30 minutes at 115°, deterioration was 8% com-
`pared to 9% in pure water solution.
`The U.S.P. (1) allows the use of glycerin in in-
`jections of deslanoside and digitoxin. A com-
`mercial product of deslanoside contains 15%
`glycerin.
`
`ETHANOL
`
`(alcohol), ethyl alcohol, finds occa-
`Ethanol
`sional use in parenteral products, particularly the
`digitalis glycosides. A commercial digitoxin
`preparation for
`intramuscular or
`intravenous
`use contains 49% alcohol. This produces pain on
`intramuscular administration. The U.S.P.
`(1)
`states that such a product can contain 5—50%
`alcohol. A digoxin preparation containing 10%
`alcohol, as allowed by the U.S.P., may be used for
`intramuscular or intravenous administration. A
`
`deslanoside product containing 7.4% alcohol is
`also available.
`
`injected subcutaneously causes con-
`Alcohol
`siderable pain followed by anesthesia.
`If injec-
`tion is made close to nerves, neuritis and nerve
`degeneration may occur.
`Injection in or near
`nerves is deliberately used to cause anesthesia in
`the treatment of severe pain. The intravenous
`anesthetic dose is 2-3 ml. of 95% alcohol/Kg.
`(83).
`Latven and Molitor (44) have reported the
`LD5o in mice to be 1973 mg./Kg. intravenously,
`and 8285 mg./Kg. subcutaneously.
`intravenous
`A commercial hydrocortisone
`product contains 50% alcohol. Mephensin in-
`jection B.P.
`(1958) contains 25% alcohol,
`its
`formula is mephenesin 10 Gm.; alcohol (95%) 25
`ml.; propylene glycol 15 n1l.; and water,pyrogen-
`free, to make 100 ml.
`(1960
`The formula for digoxin injectio