Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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4-162551-
Nasal solutions
The present invention relates to pharmaceutlcal compositions in the
form of aqueous solutions for administering human calcitonin, to the
preparation oE said pharmaceutical compositions, and to the use
thereof.
Calcitonins belong to the group of biologically active parathyroid
hormones and their structures are long polypeptide chains of varying
activity. Certain calcitonlns, e.g. human, salmon-and eel calci-
tonin, can be prepared synthetically, are commercially available,
and are widely used for the treatment oE various diseases, for
example Paget's disease, hypercalcemia or asteoporosis.
Dosage forms for the enteral administration of calcitonins, as also
for other polypeptides such as insulin, pose problems. For example,
calcitonins are rapidly degraded and are absorbed only slowly by
body fluids. For this reason only dosage forms for parenteral
administration have been used for such drugs. These dosage forms
also have their problematical aspects, especially when administered
intramuscularly or intravenously, as their suitability for self-
medicatlon is only limited and they can be painful. There is
consequently a need for more convenient dosage forms which provide
the patient with an easily manageable form of self-medication with a
bioavailability of the drug that permits effective therapy.
Nasal preparations, e~g. drops and sprays 7 for the administration of
calcitonin are disclosed in German Offenlegungsschrift 3 335 ~86.
The drawback of drops and sprays for nasal administration is,
however, that these fluids flow out of nasal cavities too quic~ly.
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In ~S patent specification 4 294 829 the proposal is made to
administer calcitonin to the nose in the form of a powdery com-
position which contains methyl cellulose, instead of using drops or
sprays. However, the administration of powders to the nose i5
normally unsuitable because of the irritation caused to dry mucous
membranes. Moreover, doses cannot well be controlled when admin-
istering powders to the nasal cavity, for example with a spray
appllcator.
Published Japanese patent publication Sho-61-126014 discloses
viscous aqueous solutions of calcitonin, e.g. salmon calcitonin,
which contain hydroxypropyl cellulose as swellable polymer. When
using human calcitonin, the solutions obtained by adding calcitonin
to a solution of hydroxypropyl cellulose are not satisfactory. In
Helvetica Chimica Acta, Vol. 53, Fasc. 8 ~1980), No. 225,
pp. 2135-2150, especial:Ly pp. 2141-2142, P. Sieber et al. describe
the formation of associates, in particular fibrillae, of h~man
calcitonin in aqueous solution. Such associates diminish the
absorption capacity of human calcitonin.
Surprisingly, it has now been found that the formatlon of fibrillae
can be avoided by lyophilising human calcitonin and dissolving the
lyophilised drug in aqueous solution, and that it is possible to
prepare a pharmaceutical composition in the form of an aqueous
solution for the nasal administration of calcitonin in readily
dosable amounts. Said pharmaceutlcal composition comprises
a) a therapeutically effective amount of lyophilised human calci-
tonin or a derivative thereof,
b) a viscosity-enhancing swellable polymer, and `
c) an aqueous carrier liquid which contains optional isotonic
components and/or further excipients.
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The general terms employed throughout this specification have the
following preferred meanings:
The term "lower" used to qualify organic radicals or groups, e.g.
lower alkyl, lower alkoxy, lower alkanoyl and the like, indicates
that such organlc radicals or groups, unless otherwise defined,
contain up to 7, preferably up to 4, carbon atoms inclusive.
The term "human calcitonin" is used in a broad sense in the context
of this description and is intended to comprise not only natural
human calcitonin as described in Helv. Chim. Acta, Vol 53, loc.
clt., which can also be obtained synthetically, but also pharma-
ceutically acceptable derivatives and analogues thereof, e.g. those
in which one or more of the amino acid groups occurring in the
natural compounds are replaced or the ~- or C-terminal group has
been structurally modified.
Human calcitonin can exist in the free form or in the form of a
pharmaceutically acceptable acid addition salt. Such salts are known
and their activity and compatibility ara comparable to those of the
free forms. Typical suitable acid addition salts are the hydro-
chlorides or acetates.
Exemplary of viscosity-enhancing swellable polymers are hydrophilic,
partially etherified cellulose derivatives as well as hydrophilic
polyacrylates, polymethylacrylates, polyethylene glycols or poly-
vinyl alcohols or mixtures of these polymers.
Hydrophilic, partially etherified cellulose derivatives are e.g.
lower alkyl ethers of cellulose having an average molar degree of
substitution (MS) greater than l and less than 3 and an average
degree of polymerisation of c. 100-5000.
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The degree o~ substitution denotes the number of hydroxy groups
replaced by alkoxy groups per glycol unit. The average molar degree
of substitution (MS~ is a mean value and indicates the number of
lower alkoxy groups per glycol unit in the polymer.
The average degree of polymerisation ~DP) is also a mean value and
indicates the average number of glycol units in the cellulose
polymer.
Typical examples of lower alkyl ethers of cellulose are cellulose
derivatives which are substituted at the hydroxymethyl group
(primary hydroxy group~ of the glucose unit forming the cellulos~
chains, and optionally at the second and third secondary hydroxy
group, by Cl-C4alkyl groups, preferably methyl or ethyl, or by
substituted C~-C4alkyl groups, e.g. 2-hydroxyethyl, 3-hydroxy-n-
propyl, carboxy~ethyl or 2-carboxyethyl.
Suitable lower alkyl ethers of cellulose are preferably cellulo~se
derivatives which are substituted at the hydroxymethyl group
(primary hydroxy group) of the glucose unit by the cited Cl-CIlalkyl
groups or by substituted Cl-CI,alkyl groups, and at the second and,
optionally, third secondary hydroxyl group by methyl or ethyl
groups.
Particularly suitable lower alkyl ethers of cellulose are methyl
cellulose, ethyl cellulose, hydroxyethyl methyl cellulose, hydroxy-
propyl methyl cellulose, hydroxyethyl ethyl cellulose, hydroxyethyl
cellulose, hydroxypropyl cellulose, carboxymethyl cellulose (in salt
form, e.g. as sodium salt), or carboxymethyl methyl cellulose (also
in salt form, e.g. as sodium salt).
Preferred lower alkyl ethers of cellulose are: methyl cellulose
(DP: c. 200-1000, MS: c. 1.4-2.0), hydroxyethyl cellulose
(DP: c. 120-1200, MS: c. 1.2-2.5), hydroxypropyl cellulose
(DP: c. 200-3000, MS: c. 1.0-3.0) and hydroxypropyl methyl cellulose
(DP: c. 200-1000, MS: c. 1~4-2~0~o
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Hydrophilic polyacrylates which can be used as viscosity-enhancing
swellable polymers have an average molecular weight of c. 8.6 x 105
to 1.0 x 106. The polyacrylic acid chains may carry short side
chains, whereby the individual commercial forms differ ln addition
to having different molecular weights. It is preferred to use
polyacrylic acid derivatives which are neutralised, e.g. wlth dilute
aqueous sodium hydroxide solution, and which are sold under the
registered trademark Carbopol~ (Goodrich), e.g. Carbopol 934 P or
Carbopol 940.
Suitable polymethacrylates are also swellable and have an average
molecular weight greater than 1.0 x 106. Preferred suitable com-
mercial forms are the polymers of methacrylic acid and methacrylates
of the Eudragit~ type, e.g. Eudragit L or Eudragit S (Rohm GmbH).
Suitable polyethylene glycols have an average molecular weight of
c. 400 to 600. Commercial forms having pharmaceutical qualities are
preferred, e.g. polyethylene glycol such as Lutrol~ (BASF), Poly-
diol~, Polywachs~ (Hiils), Polyglycol~, Lanogen~ (Hoechst), Carbowax~
(Union Carbide), Plurocol~ (Wyandotte? or Tetronic~ (Ruhlmann).
Suitable polyvinyl alcohols have an average malecular weight of
c. 28,000 to 40,000 and the properties and qualities described in
Hagers Handbuch der Pharmazeutischen Praxis (Hager's Handbook of
Pharmaceutical Practice), Springer Verlag, Yol. VIla, pp. 833-834,
referred to hereinafter as "Hager".
The ayueous carrier liquid has a pH value below 6, which is reached
after the defined amount of lyophilised calcitonin has dissolved in
the requisite amount of liquid. In accordance with the nature and
preparation of the active drug employed, the pH may be in the range
from 3 to 6 after the active drug has dissolved in the aqueous
vehicle.
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The aqueous carrier liquid preferably contains isotonic components,
e.g. ionic isotonic components such as sodium chloride, or nonionic
isotonic components such as sorbitol, mannitol or glucose (buil-
ders), and in the usual concentration employed Eor preparing
isotonic solutions and prescribed in Hager, Vol. VIIa, pp. 225-239.
It is preferred to use calcium-free isotonic sodium chloride
solution or sorbitol solution as aqueous vehicle.
The aqueous vehicle can also contain further pharmaceutically
acceptable excipients, e.g. presarvatives such as benzalkonium
chloride, surfactants for improving the flow properties, preferably
nonionic surfartants selected from the group of the polyoxyalkylene
ethers of higher alcohols, e.g. of formula
R ~ (CH2 ? n~xH
wherein R0 is the hydrophobic radical of a higher alcohol, e.g.
lauryl or cetyl alcohol, of an alkyl phenol, or of a sterol, e.g.
lanosterol, dihydrocholesterol or cholesterol, as well as mixtures
of two or more such ethers. Preferred polyoxyalkylene ethers are
polyo~yethylene and polyoxypropylene ethers carrying hydrophobic
groups (i.e. wherein n in the above formula is 2 or 3), most
preferably lauryl ether, cetyl ether and cholesterol polyoxyethylene
and cholesterol polyoxypropylene ether, as well as mixtures of two
or more such ethers.
The hydroxyl groups at the terminal radical of these above mentioned
ethers can be partially or completely acylated, e.g. with acyl
radlcals of aliphatic carboxylic acids such as acetic acid.
Preferred polyethers have a hydrophilic-lipophilic ratio (HLB value?
of c. 10 to 20, in particular from c. 12 to 16.
Particularly suitable polyethers have an average value of the
recurring units in the polyoxyalkylene moiety (bracketed s~gment of
the above formula? of from 4 to 75, preferably from 8 to 30 and,
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most preferably, Erom 16 to 26. The polyethers can be obtained by
known methods. A large selection of such products is commercially
available and sold e.g. by Amerchol under the registered trademark
Solulan~, by Kao Soap, ICI and Atlas under the registered trademarks
~malex~, Bri~ and Laureth~, and by Croda under the registered
trademark Cetomacrogel~.
Further particularly suitable surfactants are nonionic surfactants
of the fatty acid polyhydro~y alcohol ester type such as sorbitan
monolaurate, monooleate, monostearate or monopalmltate, sorbitan
tristearate or trioleate, adducts of polyoxethylene and fatty acid
polyhydroxy alcohol esters such as polyoxyethylene sorbitan mono-
laurate, monooleate, monostearate, monopalmitate, tristearate or
trioleate, polyethylene glycol fatty acid esters such as polyoxy-
ethyl stearate, polyethylene glycol 400 stearate, polyethylene
glycol 2000 stearate, in particular ethylene oxidelpropylene oxide
block polymers of the Pluronics~ type (Wyandotte).
The aqueous carrier liquid can contain still further pharmaceut-
ically acceptable excipients, e.g. essential oils for improving the
aroma, e.g. menthol, para~fin or glycerol for improving the flow
properties, sugar and/or sweeteners for improving the taste,
fragances and the like.
The nasal application of the pharmaceutical compositions permits a
comfortable and simple self-administration of human calcitonin by
the patient, so that the conventional parenteral administration by
the attendant physician can be dispensed with.
The pharmaceutical compositions have good compatibility and long
duration of action at the site of administration of the active drug.
The high viscosity of the aqueous solution effects a prolonged
retention time on the mucous membranes and thus an especially good
absorption of the drug.
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The aqueous solution for nasal application lowers the plasma calcium
and plasma phosphate level ln the blood of warm-blooded animals (man
and animals) an~ can therefore be used for treating hypercalcemia
and/or bone diseases such as Paget's disease or osteoporosis.
The dose oE human calcltonln to be administered and the concen-
tration of the drug ln the pharmaceutical composition depend on the
dlsease to be treated and on the condltlon of the patient.
The absorptlon of human calcltonln (which can be determined as blood
plasma concentration) is surprisingly high after nasal adminis-
tratlon. It can even reach values higher than those de~ermined after
lntramuscular lnjection. The dose admlnlstered can be a multiple of
the known doses conventlonally used for intramuscular admlnls-
tratlon.
Up to now, individual doses of c. 5 mg of active drug have been
administered about once daily to three times weekly when in~ecting
human calcltonin subcutaneously or lntramuscularly. Nasal adminis-
tration ln accordance wlth the practlce of this inventlon will
require, over the period of treatment, doses of c. 1.0 to 10.0 mg in
a frequency of about once daily to three times weekly. The above
doses can be adminlstered in a slngle appllcatlon, i.e. during
treatment individual doses of 1.0 to 10.0 mg of calcitonin are
administered to the nose. Alternatively, these amounts can also be
administered in divided doses two to four times daily. The total
volume of the composition for nasal administration is preferably
c. 0.1 to 0~5 ml.
The present invention preferably relates to a phaImaceutical
composition in the form of an aqueous solution for the nasal
administration of synthetic buman calcitonin, which solution has a
viscosity range of about 20-300 mPa-s (at 25~C). Said pharmaceutical
composition preferably comprises:
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a) a therapeutically effective amount of synthetic human calc~tonin,
b) c. 0.2 to 3.0 % by weight of methyl cellulose or hydroxypropyl
methyl cellulose (DP: c. 200-1000, MS: c. 1.4-2.0), and
c) an aqueaus carrier liquid containing isotonic components.
The present invention relates most preferably to a pharmaceutical
composition in the form of an aqueous solution for the nasal
administration of synthetic human calcitonin, wh:ich solu-tion has a
viscosity range of about 20-100 mPa~s (at 25C). Said pharmaceutical
composition preferably comprises:
a) a therapeutically effective amount of synthetic human calcitonin,
b~ c. 0.5 to 1.0 % by weight of methyl cellulose or hydroxypropyl
methyl cellulose (DP: c. 200-1000, MS: c. 1.4-2.0), and
c) an aqueous carrier liquid containing isotonic components.
The present i,nvention also relates to a process for the preparation
of a pharmaceutical composition in the form of an aqueous solution
containing calcitonin, which comprises mixing
a) a therapeutically effective amount of lyophilised human calci-
tonin or a derivative thereof,
b) a viscosity-enhancing swellable polymer, and
c) an aqueous carrier liquid which contains optional isotonic
components andtor additional excipients,
in a manner known per se and in any order, simultaneously or in
succession.
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A preferred embodiment of the process comprises preparing lyophil-
ised human calcitonin by e.g. dissolving the calcitonin with the
requisite amount of nonionic isotonic component (builder), e.g.
mannitol, in distilled water, ad~usting the pH o~E the solution to
c. 4-6 with a dilute aqueous sodium hydroxide solution, filtering
the solution under sterlle conditions and subsequently lyophilising
the sterile solution. The lyophilised calcitonin is added to a
solution (mucilage) containing the swellable polymer, e.g. hydroxy-
propyl methyl cellulose or methyl cellulose, and adding further
optional isotonic components such as sorbitol and preservatives such
as benzal~onium chloride, and dissolving them. The patient can then
apply this viscous solution to the nose using a drop applicator.
The pharmaceutical compositions of the invention are preferably
isotonic and the osmotic pressure can vary from 260 to 380 mOsmfkg.
The desired viscosity range can be adjustecl by addition of suitable
amounts of component b). If the viscosity is too low, the fluid
flows out of the nasal cavity too quickly. If the viscosity is too
high, the fluid becomes tacky and difficult to apply. Aqueous
solutions containing c. 0.2-3 % of methyl cellulose or hydroxypropyl
methyl cellulose (DP: c. 2~0-1000, MS: c. 1.4-2.0) have a particu- -
larly suitable viscosity range. The suitable viscosities at 20~C are
in the order of magnitude of c. 5-5000 mPa-s, preferably
20-300 mPa-s and, most preferably, 20-100 mPa-s (25~C). Reference is
made in this connection to the precise directions given in Hager,
Vol. VII, pp. 115-118, wherein the preparation of aqueous solutions
of the desired viscosity as a function of the concentration of the
respective vi~cosity-enhancing swellable polymer is described. By
addltion of active drug, osmotic salts, surfactants and other
adjuvants, the viscosity values of the pure solutions containing
swellable polymers can vary. In general, the viscous solutions must
have adequate flow propertles and ensure sufficient moistening of
the mucous membranes.
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It i5 possible to administer the pharmaceutical compositions which
contain the calcitonin a) and the swellable polymer b), together
with excipients, in solution. This liquid dosage form can be
administered to the patient by application to the nose in con-
ventional manner by means of a drop applicator. The patient can
self-administer the solution in the prescribed amount. The pharma-
ceutical compositions can also be prepared in situ, for example by
adding lyophilised calcitonin, prior to use, to a previously
prepared solution without the active drug but containing the
swellable polymer and excipients, e.g. methyl ce:Llulose or hydroxy-
propyl methyl cellulose and sorbitol or sodium chloride, and
subsequently applying the mixture to the nose. The invention also
relates to the use of the pharmaceutical compositions for the nasal
administration of human calcitonin.
The following non-limitative Examples illustrate the field of use
and operativeness of the invention.
Example 1:
a) Preparation of the lyophilised active drug
Components
CIBACALCIN~ 10.0 mg
mannitol 10.0 mg
10 mg of CIBACALCIN (human calcitonin) and 10 mg of mannitol are
dissolved at room temperature, under nitrogen, in 2.0 ml of dis-
tilled water. The pH is adjusted to 4.5 with c. 4 mg of lN aqueous
NaOH. The solution is filtered under sterile conditions through a
membrane filter ~0.2 ~m pore size) and the sterile solution is
filled into a sterile glass vial. The vial is frozen at -40C and
lyophilised in a freeze-drying apparatus.
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b) Preparation of the solution containing the swellable p~
Components
Methocel~ 90 HG 4000 cP 50.0 mg
sorbitol 500.0 mg
benzalkonium chloride 1.0 mg
dist. water 10.0 ml
Hydroxypropyl methyl cellulose (Methocel~, sorbitol and benzalkonium
chloride are mixed in distilled water. The mixture is allowed to
swell for several hours at 5C and the viscous solution is then
filtered through a Scrynel~ filter having a pore size of 10 microns.
The filtered soluiton is filled into a glass vial and sterilised,
e.g. in an autoclave. The pH of the sterilised solution is 6-7.
c) Preparation and ap~lication of the CIBACALCIN nasal solutior
(2.0 mg of lyophllised Cib~calcin/0.4 ml of swellable polymer
solution)
1 vial containing the lyophilised active drug prepared in a) is
dissolved in ,2.0 ml of the solution prepared in b). The pH of the
solution corresponds to that of the lyophilised drug. 0.4 ml of the
viscous CIBACALCIN solution is applied with a drop applicator to the
nose (both nostrils) of the recumbent patient.
le 2:
a) In accordance with Example 1 a), lyophilised active drug formu-
lations are prepared from 10 mg of Cibacalcin (without the
addition of mannitol), 10 mg of Cibacalcin and 30 mg of mannitol,
and 10 mg of Cibacalcin and 10 mg of mannitol and 2 mg of
hydroxypropyl methyl cellulos~ (Methocel~). The pH of each
solution to be lyophilised is adjusted to 3.5-6.0 with dilute
aqueous sodium hydroxide solution.
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b) As described in Example 1 b), solutions containing swellable
polymer are prepared from 20 to 100 mg of hydroxypropyl methyl
cellulose (Methocel), 500 mg of sorbltol and 1.0 mg of benzal-
konium chloride, or from 20 to 100 mg of hydroxypropyl cellulose
(~lucel~), 500 mg of sorbitol and 1.0 mg of benzalkonium chlo-
ride.
c) In accordance with the procedure of Example 1 c), the solutions
prepared in b) are added to the lyophilised drug formulations
prepared in a) and applied to the nose.
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