(12) Ulllted States Patent
`Chauveau et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 6,326,401 B1
`Dec. 4, 2001
`
`US006326401Bl
`
`(54) FORMULATION FOR THE OROMUCOSAL,
`IN PARTICULAR PERNASAL, ROUTE
`
`(58) Field of Search .................................. .. 514/2, 9, 966,
`514/547
`
`(75)
`
`Inventors: Jacques Cha11vea11; Pascal Meyer;
`Jacques Barbet; Michel Delaage, all
`Of Marseilles (FR)
`
`_
`(36)
`
`.
`References cued
`FOREIGN PATENT DOCUMENTS
`
`(73) Assignee:
`
`Immunotech, Marseilles (FR)
`
`0 457 701
`WO 94/08622
`
`11/1991 (EP) .
`4/1994 (WO) .
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 09/225,742
`(22)
`Filed:
`Jam 6, 1999
`
`(30)
`
`Foreign Application Priority Data
`
`(FR) ................................................ .. 98 00574
`Jan. 15, 1998
`(51)
`Int. Cl.7 ................................................... .. A61K 31/22
`(52) U.S. Cl.
`........................................... .. 514/547; 514/966
`
`Primary Exam1'ner—Zohreh Fay
`(74) Attorney, Agent, or Firm—BroWdy and Neimark
`
`ABSTRACT
`(37)
`A liquid pharmaceutical formulation for administration by
`the oro-mucosal route, comprising at
`least one non-
`polypeptidic active substance and less than 5% W/W of
`capryl caproyl macrogol glycerides, process for its prepa-
`ration and it uses‘
`
`20 Claims, 1 Drawing Sheet
`
`   
`


`
`Lannett Holdings, Inc. LAN 1004A
`
`

`
`U.S. Patent
`
`Dec. 4, 2001
`
`US 6,326,401 B1
`
`2.0
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`Figure 1
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`0
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`30
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`BO
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`90
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`Figure 2
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`

`
`US 6,326,401 B1
`
`1
`FORMULATION FOR THE OROMUCOSAL,
`IN PARTICULAR PERNASAL, ROUTE
`FIELD OF THE INVENTION
`
`2
`in
`achieving the fastest possible medicamentous effect,
`addition with a good reproducibility of the administration.
`
`SUMMARY OF THE INVENTION
`
`The present invention relates to a new formulation for the
`oromucosal, in particular the pernasal, route.
`BACKGROUND OF THE INVENTION
`
`The oral administration route for medicamentous active
`
`10
`
`substances, in particular solid active substances, is by far the
`most widely used. In fact, solid forms administered by the
`oral route are particularly suitable for ambulatory treatment,
`and this type of formulation usually offers a good stability
`with respect to time. IIowever, this administration route, in
`which the active substance is administered by the buccal
`route,
`to be delivered into the stomach and the small
`intestine, has its limits, in particular because a large number
`of active substances are degraded in the gastrointestinal
`tract. As a result, it is often necessary to administer to the ,
`patient a dose of active substance which is considerably
`higher than the dose actually necessary for the activity of the
`product such as can be obtained by parenteral, intravenous,
`subcutaneous or intramuscular administration, for example,
`which leads to an increase in the volume of active substance
`
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`that
`The Applicant has now discovered, surprisingly,
`particular pharmaceutical formulations for the oro-mucosal
`route, in particular for the nasal route, are a solution which
`is particularly suitable for the problems described above.
`The present invention thus relates to a liquid pharmaceu-
`tical formulation for administration by the oro-mucosal, in
`particular nasal, route, characterized in that it comprises at
`least one non-polypeptidic active substance and less than 5%
`W/W of capryl caproyl macrogol glycerides (sometimes
`referred to as C8—C10 saturated polyglycolysated
`glycerides).
`W0-A-94/08622 discloses pharmaceutical formulations
`comprising an active substance and saturated or unsaturated
`polyglycolysed glyceride, but
`the active substance is a
`polypeptide of about 32 amino acids, particularly calcitonin,
`and the saturated or unsaturated polyglycolysed glycerides
`represents 7% or more, generally 35 to 90% by weight and
`more of the formulation which usually is a gel or is solid.
`Whenever these formulations comprise caproyl macrogol
`glycerides such as Labrasol, such compounds represent 20%
`or more of the formulation.
`
`invention and hereafter, “oro-mucosal
`In the present
`route” is understood as meaning the mucosa lining the
`buccal, nasal or pharyngeal cavities.
`“Polypeptidic active substance” is understood as meaning
`an active substance comprising a chain of at least 10 amino
`acids.
`
`The administration of an active substance by the oro-
`mucosal route can involve administration of an effective
`dose of active substance in the form of a single dose or
`fractionated doses.
`
`The active substance can be of any nature with the above
`proviso, and there may be mentioned,
`for example,
`antibiotics, bacteriostatics, antihistaniines, analgesics and
`medicaments for cardioangiology, such as
`antihypertensives, diuretics, vasodilators and vasoconstric-
`tors. The active substance can also be for endocrinology, and
`in this respect
`there may be mentioned oestrogens,
`oestroprogestogens, glucocorticoids, hypothalamic or hypo-
`physial hormoncs or progcstogcns. It can also be an active
`substance for infectiology, such as antibiotics or antibacte-
`rial agents, antiviral agents or vaccines. It can also be a
`compound for neurology, such as analgesics.
`The active substance can be, in particular, a compound
`derived from an endogenous mediator, in particular one of
`those described in EP-A-0 457 701, that is to say a derivative
`of biologically active molecules containing a primary amine
`function and a hydroxylated nucleus or one of their addition
`salts with mineral or organic acids, of the formula (I):
`
`[R’R"N—A—B—O—CH2—CO],,Rl
`
`(1)
`
`to be administered. It is therefore necessary to manufacture
`considerably more active substance that is actually neces-
`sary in theory to obtain the desired therapeutic effect.
`For this reason, new pharmaceutical forms are still being
`sought,
`in particular for active substances which are
`degraded particularly in the gastrointestinal tract.
`Alternatives to parenteral administration, which involves
`sterile equipment and also aseptic conditions during the
`administration, which limits commercial distribution, are
`also still being sought.
`Among the formulations suitable for ambulatory use,
`formulations for administration via the intermediary of the
`bucco-pharyngcal or nasal mucosa are also well known.
`The formulations for
`the nasal
`route are generally
`intended for treatment of conditions of the nasal and rhi-
`
`nopharyngeal mucosa, and are thus essentially reserved for
`local treatment. This pharmaceutical form is rarely used for
`more general uses.
`The formulations for the buccal route are generally
`intended for local treatment of conditions of the buccal
`mucosa, such as aphthae. This pharmaceutical form is also
`rarely used for systemic uses.
`It would thus be desirable to have available an eifective
`
`pharmaceutical formulation which is particularly suitable
`for ambulatory treatment, in particular suitable for medica-
`ments which have a tendency to be degraded particularly by
`oral administration. Such a pharmaceutical formulation
`should cause neither irritation nor lesion of the mucosa.
`
`Practice in the pharmaceuticals industry demands a large
`number of quality controls, and it would also be desirable if
`the nature of such a formulation is such that it does not
`interfere with direct assay of the active substance, such that
`it is easy to follow the product in a manufacturing chain or
`to identify the product. The phase of extraction of the active
`substance for its characterization would thus be avoided.
`
`60
`
`or of the formula (II)
`
`It would also be desirable to administer significant doses
`of active substances in volumes which are as reduced as
`possible.
`In the majority of pathologies, it is desirable to obtain the
`fastest possible effect. For this reason, a particularly advan-
`tageous pharmaceutical formulation would be capable of
`
`65
`
`R'R"N A B 0 CH2
`B—A—NR'R"
`
`CO NH R NH CO CH2 0
`(11)
`
`in which
`
`n represents an integer from 1 to 10; Arepresents a linear
`or branched alkylene chain containing 1 to 5 carbon
`atoms; B represents an aromatic nucleus containing 6 to
`
`

`
`US 6,326,401 B1
`
`3
`10 optionally substituted carbon atoms and optionally a
`heteroatom; R1 represents an amino radical or an
`alcohol radical chosen from phenols, which are option-
`ally substituted, and aliphatic C1—C15 alcohols; R‘ and
`R" represent an alkyl radical containing 1 to 5 carbon
`atoms or a hydrogen atom and R represents a divalent
`diamine or polyamine radical, in particular the deriva-
`tives mentioned as preferred in this patent, and espe-
`cially tryptamine 5-0-carboxymethyl-tyrosyl-
`glycinamidc (IS 159), callcd “IS 159” below, or one of
`its salts.
`The active substance can also be, in particular, an anti-
`migraine active substance, such as a triptan, such as
`sumatriptan or zolmitriptan.
`The active substance may represent important amounts in
`the formulation, up to the limit of solubility of the active
`substance in the said formulation.
`
`The capryl caproyl macrogol glycerides are also known
`by the name of saturated polyglycosylated C8—Cm glycer-
`ides. Some of them are marketed by the company GATTE-
`FOSSE under the name Labrasol®.
`Capryl caproyl macrogol glycerides are mixtures of
`monoesters, diesters and triesters of glycerol and monoesters
`and diesters of macrogol with an average molecular weight
`of between 200 and 400.
`
`These compounds can also be obtained by partial alco-
`holysis of medium-chain triglycerides using macrogol, or by
`esterification of glycerol and macrogol with caprylic acid
`and capric acid or of a mixture of esters of glycerol and an
`ethylene oxide condensate with caprylic acid and capric
`acid.
`
`In preferred embodiments of the invention, lcss than 3%
`weight/weight of capryl caproyl macrogol glycerides is used
`in a finished pharmaceutical formulation, preferably 0.5 to
`2.5%, and especially 1.5 to 2.2%.
`the
`In other preferred embodiments of the invention,
`above formulation also comprises at least one preservative.
`The preservative which can be used is any preservative
`suitable for achieving a homogeneous formulation, and
`especially an alkali metal benzoate, in particular sodium
`benzoate. The use of sodium benzoate as the preservative
`gives particularly interesting results. In fact, for example by
`using benzoic acid or methyl and propyl
`parahydroxybenzoate, an instability of the mixture is
`observed, manifesting itself, for example, by flocculation or
`by phase separation.
`The preservative can be present in the proportions indi-
`cated in the various pharmacopoeias, and in particular in
`proportions ranging from 0.05% to 1.5% by weight for the
`benzoates, expressed as benzoic acid,
`in particular 01 to
`0.3% by weight, and in particular about 0.2% by weight in
`a finished pharmaceutical formulation.
`the
`In other preferred embodiments of the invention,
`above formulation also comprises an isotonicity agent which
`is well known in the prior art, and in particular sodium
`chloride.
`In the case where sodium chloride is used, its proportion
`is advantageously about 9 parts per thousand by weight in a
`finished pharmaceutical formulation.
`In still further preferred embodiments of the invention,
`the above formulation is a liquid nasal formulation, charac-
`terized in that it has a pH of between 4 and 9, in particular
`between 5 and 8.
`
`In still further preferred embodiments of the invention,
`the above liquid nasal formulation comprises 5 to 100 mg/ml
`of an above active substance. A unit dose will be,
`for
`example, 0.1 to 20 mg of an active substance.
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`4
`The final volume of a liquid formulation according to the
`invention is advantageously adjusted with the aid of water
`for injectable preparations.
`The active substance is preferably dissolved in the for-
`mulation.
`Other excipients usually employed in these pharmaceuti-
`cal formulations of this type, such as aqueous vehicles,
`emulsifiers and non—aqueous vehicles, can also be incorpo-
`rated into the formulations according to the invention.
`The present invention also relates to an above liquid
`pharmaceutical
`formulation, characterized in that
`it
`comprises,
`in aqueous solution or in the presence of a
`pharmaceutically acceptable solvent,
`tryptamine 5-O-
`carboxymethyl-tyrosyl-glycinamide (IS 15 9), or of one of its
`salts, in a dose which is effective for the pemasal route, and
`in that it has a pH of 4 to 8, in particular 6 to 7.
`The present invention also relates to an above liquid
`pharmaceutical formulation, characterized in that it has a
`concentration of 5 to 100 mg tryptamine 5-O-
`carboxymethyl—tyrosyl—glycinamide per ml, and in that a
`unit dose comprises between 0.1 and 20 mg tryptamine
`5-O-carboxymethyl-tyrosyl-glycinamide.
`The present invention also relates in particular to an above
`liquid pharmaceutical formulation for administration by the
`nasal
`route, comprising about 4 g tryptamine 5-O-
`carboxymethyl-tyrosyl-glycinamide (IS 159), 0.9 g NaCl, 2
`g Labrasol®. 0.1175 g sodium benzoate, and water for an
`injectable preparation qsp 100 g, the final pH being between
`pH 6 and pH 7.
`The present invention also relates to a process for the
`preparation of a formulation described above, characterized
`in that the active substance or substances is or are mixed
`
`with capryl caproyl macrogol glyccridcs and with the other
`desired pharmaceutically acceptable excipients by methods
`which are known per se.
`The formulations according to the invention have remark-
`able properties.
`Firstly, as regards the bioavailability of the active
`substance, and taking the subcutaneous route as the refer-
`ence route (100%), during tests carried out, whereas by
`administration of an equal amount of active substance by the
`oral route only 1 to 5% of the effect obtained by the
`subcutaneous route is obtained, about 10% of the effect
`obtained by the subcutaneous route is obtained by the
`sublingual route, and better still an effect equal to about 50%
`of the effect obtained by the subcutaneous route is obtained
`by the nasal route.
`In addition, the effect was obtained faster by the nasal
`route than by the subcutaneous route.
`Furthermore, the formulations according to the invention
`offer the possibility of administration of significant doses of
`active substance in small volumes.
`
`Moreover, an excellent reproducibility of the effect
`obtained between different individuals is observed by using
`a formulation according to the invention.
`In addition, by using a formulation according to the
`invention, it is found that after nasal administration this does
`not have the tendency to run, which also achieves good
`comfort to the user, avoiding him having to wipe his nose,
`or indeed becoming irritated.
`Moreover, it is possible to carry out an assay of the active
`substance directly in the formulation according to the
`invention, without having the need to extract it. This char-
`acterization and assay can be carried out, in particular, by
`high performance liquid chromatography (HPLC) and by
`ultraviolet spectrometry.
`The packaged formulations of the invention can be in the
`conventional forms used for nasal formulations, that is to
`
`

`
`US 6,326,401 B1
`
`5
`in particular, nebulizers, predosed or non-predosed
`say,
`sprays, dropper bottles, multidose bottles or monodose
`bottles.
`
`The present application also relates to the use of a capryl
`caproyl macrogol glyceride in an amount of less than 5% in
`a liquid pharmaceutical formulation for administration by
`the oro-mucosal route.
`
`The present application also relates to a method for
`administration by the oro-mucosal route of at least one
`active substance, characterized in that the active substance
`or substances is or are mixed with capryl caproyl macrogol
`glycerides and with the other desired pharmaceutically
`acceptable excipients by methods which are known per se
`and the pharmaceutical formulation obtained in then
`administered, preferably on to the nasal mucosa.
`Finally, the present application relates to:
`The use of a capryl caproyl macrogol glyceride to
`increase the solubility of a product.
`The use of a capryl caproyl macrogol glyceride to
`increase the absorption of an active substance into the
`blood.
`
`The use of a capryl caproyl macrogol glyceride to
`increase the rate of absorption of an active substance
`into the blood.
`
`The use of a capryl caproyl macrogol glyceride to
`increase the bioavailability of an active substance.
`The use of a capryl caproyl macrogol glyceride in a liquid
`formulation to limit the loss of active substance due to
`
`running out of the said liquid formulation.
`The use of a capryl caproyl macrogol glyceride in a
`formulation to ensure a better reproducibility of the
`nasal administration.
`
`A method for treatment of a human suffering from or
`subject to migraines, which comprises the administra-
`tion of an above formulation in which the active
`substance is a antimigraine agent, in particular by the
`pernasal route.
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 shows the result of HPLC analysis of the solution
`of example 1 under the conditions specified in this example.
`FIG. 2 shows the concentration of IS 159 as a function of
`
`time and the corresponding standard deviation.
`The example which follow illustrate the present inven-
`tion.
`
`Example 1
`
`Formulation Examples
`
`a) Solution for nasal administration
`0.9 g sodium chloride and 0.235 g sodium benzoate are
`introduced into 94.67 g water for injectable preparations.
`The mixture is stirred until dissolution is complete. 2 g
`Labrasol® are then introduced, while stirring slowly. 4 g IS
`159 are then added until dissolution is complete. The solu-
`tion is then filtered over 0.22 gm cellulose acetate.
`The aqueous solution obtained is then divided among
`nebulizer bottles.
`
`b) Control solution
`As the control solution, preparations in which the Labra-
`sol® was replaced by 2 ml distilled water were also pre-
`pared.
`c) Sublingual tablets
`A formulation having the following composition was
`prepared:
`
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`IS 59
`Labrasol ®
`
`10 mg
`2 mg
`
`lactose, microcrystalline cellulose,
`Other excipients:
`pregelatinized maize starch, colloidal silica, magne-
`sium stearate.
`
`Example 2
`
`Assay of the Active Substance in the Presence of
`Labrasol® By UV-Visible Spectrophotometry
`
`The solution of example 1 is diluted 1/800 in distilled
`water. The absorbances measured at 280 nm and at 350 nm
`are identical to those obtained in the absence of Labrasol®.
`The use of Labrasol® therefore does not interfere with the
`
`assay of the active substance by UV-visible spectrophotom-
`etry.
`
`Example 3
`
`Assay and Analysis of the Active Substance in the
`Present of Labrasol® By HPLC
`
`The solution of example 1 is diluted 1/200 by the isocratic
`eluent made up of 90 volumes of triethylaminephosphoric
`acid (TPA) pH 2.5 and 10 volumes of acetonitrile (ACN) and
`is analysed by HPLC (high performance liquid
`chromatography) at 210 nm.
`FIG. 1 shows the result of the analysis. The scale on the
`abscissa represents the elution parameters expressed in min
`(or ml, since the flow rate is 1 ml/min) and the scale on the
`ordinate represents the absorbance.
`The same procedure is followed with the control solution.
`The profile of the high performance liquid chromatography
`and the height of the peaks are identical in the two cases.
`The use of Labrasol® thus does not change the criteria of
`direct analysis of the active substance and the preservative
`by the HPLC method.
`
`Example 4
`
`Bioavailability Test
`
`After nasal administration in man of an equal volume of
`the solution and control solution of example 1, the serum
`concentrations of IS 159 were measured as a function of
`time.
`
`The presence of Labrasol® increases the absorption
`(Cmax) of IS 159 and reduces the delay in the appearance of
`IS 159 in the serum (apparent Tmax observed: control 30
`min, with Labrasol® 10 to 15 min).
`The use of Labrasol® considerably increases the bioavail-
`ability of IS 159 by the nasal route, evaluated by the area
`under the curve (AUC) of the concentration of IS 159 as a
`function of the time which elapses for an observation period
`of 4 hours, from 12 to 85 ng/ml/h.
`
`Example 5
`
`Reproducibility of the Compared Bioavailability of
`the Aqueous Nasal Solution Plus Labrasol®
`The serum concentration of IS 159 as a function of time
`were measured on a group of 8 subjects after nasal admin-
`istration of an identical amount of 100 ,ul (that is to say 4 mg
`active substance IS 159) of the solution of example 1.
`
`

`
`US 6,326,401 B1
`
`7
`The interindividual and intraindividual reproducibilities
`of the pharmacokinetic parameters of IS 159 in aqueous
`nasal solution in the presence of Labrasol® prove to be
`good.
`The serum concentrations of IS 159 as a function of time
`
`were also measured on a group of 8 subjects after nasal
`administration of identical quantities of the solution of
`example 1 (4 mg active substance IS 159) during sessions
`separated with respect to time.
`The interindividual and intraindividual reproducibilities
`of the pharmacokinetic parameters of the solution of
`example 1 prove to be equally good.
`
`Example 6
`
`nStudy of the Dose/Effect and Reproducibility of
`the Compared Bioavailability
`The serum concentrations of IS 159 as a function of time
`were measured on the same individual after nasal adminis-
`tration of increasing amounts of the solution of example 1
`(corresponding to 4 mg and 7 mg active substance).
`The serum concentrations of IS 159 as a function of time
`were also measured on groups of 8 subjects after nasal
`administration of increasing amounts of the solution of
`example 1 (corresponding, for example, to 4 mg and 7 mg
`active substance IS 159).
`FIG. 2 shows the concentration of IS 159 measured,
`expressed in ng/ml, as a function of time, expressed in
`minutes, and the corresponding standard deviation. The
`black squares represent the dose of 4 mg and the white
`squares represent the dose of 7 mg.
`The ratios of the AUCs and the maximum concentrations
`
`obtained prove to be constant and high.
`The bioavailability and absorption of this nasal formula-
`tion are found to be significant. This high absorption fur-
`thermore proves to be very fast.
`The good intra—individual and interindividual reproduc-
`ibility of the pharmacokinetic parameters remain preserved.
`
`Example 7
`
`Comparison Between S11bling11al Formulations
`Without and With Labrasol
`
`IS 159 was administered by the sublingual route.
`a) Assay and analysis
`The supernatants of dissolution, with the aid of 1 ml
`distilled water, of the sublingual tablets of example 1 dosed
`with 10 mg IS 15 9 with 2% Labrasol® and of tablets without
`Labrasol® (2% lactose) were compared.
`After dilution to 1/200 in distilled water of the dissolution
`supernatants, the absorbance was measured by UV-visible
`spectrophotometry in both cases.
`The absorbances measured at 280 nm and at 350 nm prove
`to be identical.
`
`Labrasol® therefore does not trap the active substance.
`The use of Labrasol® does not interfere with the assay of
`IS 159 by UV-visible spectrophotometry, and does not
`interfere with the assay of the active substance contained in
`the tablet.
`
`After dilution to 1/50 in the isocratic eluent made up of 90
`volumes of triethylaminephosphoric acid (TPA) pH 2.5 and
`10 volumes of acetonitrile (ACN), HPLC analysis of the
`samples was carried out.
`The HPLC profile obtained on a ;tBondapack column is
`identical in the two cases.
`
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`8
`The use of Labrasol® therefore does not change the
`criteria of direct analysis of the active substance by the
`HPLC method.
`
`b) Compared bioavailability of sublingual formulations
`without and with Labrasol®
`
`The serum concentrations of IS 159 as a function of time
`
`were measured on healthy volunteer subjects. These subjects
`received an identical amount of active substance IS 159 ('10
`mg) in the form of tablets in the absence or presence of
`Labrasol® (2%) by sublingual administration.
`The presence of Labrasol® increases the absorption
`(Cmax) of IS 159 and decreases the delay in the appearance
`of IS 159 in the serum (apparent Tmax observed: control 45
`min, with Labrasol® 35 min).
`The use of Labrasol® considerably increases the bioavail-
`ability of IS 159 by the sublingual route, evaluated by the
`area under the curve (AUC) of the concentration of IS 159
`measured as a function of time for an observation period of
`6 hours, from 0.42 for the control (2% lactose) to 9.72
`ng/ml/h with Labrasol®.
`
`Example 8
`
`Comparison Between the Aqueous Nasal Solution
`and the Sublingual Formulation
`
`The serum concentrations of IS 159 as a function of time
`were measured on healthy volunteer subjects. The subjects
`received an identical amount of 10 mg IS 159 in the form of
`tablets with the formula indicated in example 7 comprising
`2% Labrasol®, or by nasal administration of the solution of
`example 1.
`
`In the presence of Labrasol® and at the same concentra-
`tion of active substance, the aqueous nasal solution has a
`considerably better bioavailability than the corresponding
`sublingual formulation. The bioavailability of IS 159 by the
`nasal route, evaluated by the area under the curve (AUC) of
`the serum concentration of IS 159 evaluated from time 0 to
`infinity, is 166 ng/ml/h, against 12 ng/ml/h for the sublingual
`formulation with Labrasol®, which itself already showed a
`considerably better bioavailability than the sublingual for-
`mulation without Labrasol®.
`
`The terminal half-life of IS 159 remains constant and
`
`close to 2 hours and thirty minutes.
`
`Example 9
`
`Compared Bioavailability of the Aqueous Nasal
`Solution/aqueous Subcutaneous Solution
`
`The serum concentrations of IS 159 as a function of time
`were measured on healthy volunteer subjects. These subjects
`received an identical amount of 4 mg IS 159 by the subcu-
`taneous route (sc) or by nasal administration of the solution
`of example 1.
`
`The bioavailability of the aqueous nasal solution of IS 159
`comprising Labrasol is found to be significant and faster
`than by the subcutaneous route.
`
`The terminal half-life of IS 159 is not changed signifi-
`cantly.
`
`The administration of the aqueous nasal solution therefore
`proves to be reproducible and pleasanter than the subcuta-
`neous administration.
`
`

`
`US 6,326,401 B1
`
`9
`
`AUC/dose
`(h.ng/ml)(mg dose
`IS 159)
`14
`36
`ratio = 39%
`
`Mean nasal
`Mean s.c.
`Nasal/s.c.
`
`Tmax
`Cmax/dose
`in minutes
`ng/ml
`15
`11
`30
`20
`ratio = 55% reduced
`
`Terminal
`half-life
`2.5 h
`2.5 h
`not
`changed
`
`COMPARISON EXAMPLE
`
`The sodium benzoate in example 1 was replaced by 0.15
`g benzoic acid, 0.2 g methyl parahydroxybenzoate and 0.2
`g propyl parahydroxybenzoate. In the three cases, an insta-
`bility of the solution, in particular of the flocculation and
`phase separation type, was observed.
`What is claimed is:
`
`10
`
`15
`
`1. A liquid pharmaceutical formulation for administration '
`by the oro-mucosal route, comprising at
`least one non-
`polypeptidic active substance and less than 5% W/W of
`capryl caproyl macrogol glycerides.
`2. Aliquid pharmaceutical formulation according to claim
`1, for administration by the nasal route.
`3. Aliquid pharmaceutical formulation according to claim
`1, packaged in a form used for nasal formulations, such as
`nebulizers, predosed or non-predosed sprays, dropper
`bottles or monodose or multidose bottles.
`
`25
`
`4. A liquid pharmaceutical formulation according to
`claims 1, comprising 3% or less weight/weight of capryl
`caproyl macrogol glycerides in a finished formulation.
`5. Aliquid pharmaceutical formulation according to claim
`1, comprising from 0.5 to 2.5% weight/weight of capryl
`caproyl macrogol glycerides in a finished formulation.
`6. Aliquid pharmaceutical formulation according to claim
`1, further comprising a preservative.
`7. Aliquid pharmaceuticalformulation according to claim
`1, further comprising alkali metal benzoate as a preservative.
`8. Aliquid pharmaceutical formulation according to claim
`1, comprising a derivative of biologically active molecules
`containing a primary amine function and a hydroxylated
`nucleus or one of their addition salts with mineral or organic
`acids, of the formula (I):
`
`[R'R"N—A—B—()—CH2—C()],,R1
`
`(1)
`
`or of the formula (II)
`
`R'R"N A B 0 "H2
`B—A—NR'R"
`
`CO NH R NH co "H2 0
`(11)
`
`in which
`
`n represents an integer from 1 to 10; Arepresents a linear
`or branched alkylene chain containing 1
`to 5 carbon
`atoms; B represents an aromatic nucleus containing 6 to
`10 optionally substituted carbon atoms and optionally a
`heteroatom; R1 represents an amino radical or an
`alcohol radical chosen from phenols, which are option-
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`10
`ally substituted, and aliphatic C1—C15 alcohols; R‘ and
`R“ represent an alkyl radical containing 1 to 5 carbon
`atoms or a hydrogen atom and R represents a divalent
`diamine or polyamine radical.
`9. Aliquid pharmaceutical formulation according to claim
`1, comprising, in aqueous solution or in the presence of a
`pharmaceutically acceptable solvent,
`tryptamine 5-O-
`carboXymethyl—tyrosyl—glycinamide (IS 159), or of one of its
`salts, in a dose which is effective by the pernasal route, and
`in that it has a pH of 4 to 8.
`10. A liquid pharmaceutical formulation according to
`claim 9, wherein the pH of the formulation is from 6 to 7.
`11. A liquid pharmaceutical formulation according to
`claim 9, comprising from 5 to 100 mg tryptamine 5-0-
`carboxymethyl-tyrosyl-glycinamide (IS 159) per ml, and
`wherein a unit dose comprises between 0.1 and 20 mg
`tryptamine 5-O-carboxymethyl-tyrosyl-glycinamide (IS
`159).
`12. A liquid pharmaceutical formulation according to
`claim 1 for administration by the nasal route, comprising
`about 4 g tryptamine 5-O-carboXymethyl-tyrosyl-
`glycinamide (IS 159), 0.9 g NaCl, 2 g Labrasol®, 0.1175 g
`sodium benzoate, and water for an injectable preparation qsp
`100 g, the final pH being between pH 6 and pH 7.
`13. A process for the preparation of a liquid pharmaceu-
`tical formulation according to claim 1, comprising mixing
`active substance or substances with the capryl caproyl
`macrogol glycerides and with the other desired pharmaceu-
`tically acceptable excipients by conventional methods.
`14. A liquid pharmaceutical formulation according to
`claim 8, comprising 3% or less weight/weight of capryl
`caproyl macrogol glycerides in a finished formulation.
`15. A liquid pharmaceutical formulation according to
`claim 14, comprising, in aq11eo11s solution or in the presence
`of a pharmaceutically acceptable solvent, tryptamine 5-O-
`carboxymethyl-tyrosyl-glycinamide (IS 15 9), or of one of its
`salts, in a dose which is effective by the pernasal route, and
`in that it has a pH of 4 to 8.
`16. A liquid pharmaceutical formulation according to
`claim 8, comprising, in aqueous solution or in the presence
`of a pharmaceutically acceptable solvent, tryptamine 5-O-
`carboxymethyl-tyrosyl-glycinamide (IS 15 9), or of one of its
`salts, in a dose which is effective by the pernasal route, and
`in that it has a pH of 4 to 8.
`17. A liquid pharmaceutical formulation according to
`claim 4, comprising, in aqueous solution or in the presence
`of a pharmaceutically acceptable solvent, tryptamine 5-O-
`carboXymethyl-tyrosyl-glycinamide (IS 15 9), or of one of its
`salts, in a dose which is effective by the pernasal route, and
`in that it has a pH of 4 to 8.
`18. A liquid pharmaceutical formulation according to
`claim 15, wherein the pH of the formulation is from 6 to 7.
`19. A liquid pharmaceutical formulation according to
`claim 16, wherein the pII of the formulation is from 6 to 7.
`20. A method of treatment comprising administering a
`liquid pharmaceutical composition in an amount of less than
`5% W/W of capryl caproyl macrogol glyceride in said liquid
`pharmaceutical formulation by the oro-mucosal route.
`*
`*
`*
`*
`*