Description
Title of Invention: NON-AQUEOUS OILY INJECTABLE FOR¬
MULATION EXHIBITING PRESERVATIVE EFFICACY
Technical Field
[1] The present invention relates to an injectable formulation including a therapeutically
effective amount of an active ingredient, an oil containing the active ingredient, a hydrophilic
excipient non-phase separable from the oil and/or an oil- affinitive
(commonly referred to as 'lipophilic') preservative combined with the hydrophilic
excipient, which may exhibit higher preservative efficacy, compared to administration
of the preservative alone.
Background Art
[2] In the case where a medication does not have suitable anti-microbial activity, an in
jectable formulation containing the medication should be provided with an anti
microbial preservative or any suitable additive, to prevent proliferation or con
tamination of microorganisms.
[3] Specifically, a multiple-dose injection may be a formulation wherein the injection is
drawn (or extracted) several times from a vial or, otherwise, an injection needle is
stuck in a cartridge several times, thus being used. In order to prepare against con
tamination of the microorganisms possibly occurring while repeatedly using, high an
timicrobial activity is needed.
[4] Although numerous studies and investigations into aqueous injectable formulations
having improved preservative abilities have been implemented, a non-aqueous in
jectable formulation with high preservative ability has yet to be disclosed.
Disclosure of Invention
Technical Problem
[5] The present inventors have conducted extensive and intensive studies and various ex
periments and found that an injectable formulation with specific constitutional com
position as described below according to the present invention may surprisingly exhibit
higher preservative ability, compared to administration of a lipophilic preservative
alone, thereby completing the present invention.
Solution to Problem
[6] Accordingly, the present invention provides an injectable formulation that includes a
physiologically effective amount of active ingredient, oil containing the active in
gredient, a hydrophilic excipient non-phase separable from the oil, and a lipophilic
preservative combined with the hydrophilic excipient, which exhibits higher
preservative ability (hereinafter, referred to as 'preservative efficacy'), compared to administration
of the lipophilic preservative alone.
[7] The injectable formulation is usually used in cases where a desired level of efficacy
of the medication should be rapidly attained, the medication cannot be orally ad
ministered, the medication is modified by digestive juices or less absorbed, and/or the
medication stimulates mucosa of gastrointestinal tract (GI tract), and may be directly
administrated via intradermal, subcutaneous, intramuscular, intravenous or intra
arterial routes. Such an injectable formulation should be sterile and a multi-dose for
mulation must have preservative efficacy to maintain a sterile condition over the period
of use.
[8] Specifically, a non-aqueous oily injectable formulation may be a formulation that is
used as a solvent for dissolving a water-insoluble drug or, otherwise, adopts oil as a
medium for dispersing or suspending an active ingredient in a powder form, which is
insoluble in the oil. A multi-dose injectable formulation based on the foregoing must
ensure high preservative efficacy and, therefore, may have advantages of enabling
repetitive administration to thus improve convenience in use and reducing waste of
drug and/or receptacles for drugs. However, careful attention to stability and storage of
the formulation is necessary.
[9] Hereinafter, the present invention will be described in more detail.
[10] An active ingredient in a therapeutically effective amount may be a protein or peptide
drug and hyaluronic acid or an inorganic salt thereof. Another examples of the active
ingredient may include; testosterone ester, progesterone ester, haloperidol ester,
nandrolone decanoate, boldenone undecylenate, etc., without being particularly limited
thereto.
[11] The active ingredient described in the present invention may be included in oil. More
particularly, the active ingredient may be dissolved, dispersed or suspended in oil,
however, such a way of including the active ingredient in the oil is not particularly
limited to the foregoing.
[12] According to one preferred embodiment, the active ingredient may be present in a
particle form covered with a lipophilic material on the surface thereof and dispersed or
suspended in oil. Such a lipophilic material may be selected from a group consisting of
lipids, lipid derivatives, fatty acid, fatty acid salts, fatty acid ester derivatives, other
fatty acid derivatives, surfactants, lecithin, hyaluronic acid and waxes. In this regard,
the content of Korean Patent No. 0329336 owned by the present applicant, is in
corporated by reference.
[13] The term 'therapeutically effective amount' means an amount of a drug administered
to alleviate or reduce at least one or more of symptoms of a disorder to be treated using
the drug, or an amount of an active ingredient effective to delay initiation of clinical
markers or symptoms of a disease to be prevented. That is, the therapeutically effective
amount practically means an amount expressing: (1) inversion effects of the progress
of disease; (2) inhibitory effects of the progress of disease over a certain extent; and/or
(3) effects of moderately alleviating (preferably eliminating) at least one or more
symptoms related to a disease. The therapeutically effective amount may be de
termined from empirical results by testing a compound in vivo and/or in vitro model
systems.
[14] According to the present invention, the oil may be a solvent in which the active in
gredient is dissolved, dispersed and/or suspended and may include, for example;
monoglyceride, diglyceride, triglyceride, medium chain triglyceride (MCT), sesame
oil, Arachis oil (peanut oil), castor oil, olive oil, corn oil, cotton seed oil, soybean oil,
peppermint oil, coconut oil, palm seed oil, safflower oil, etc., without being p ar
ticularly limited thereto. These substances may be used alone or as a mixture of two or
more thereof.
[15] According to the present invention, a lipophilic preservative is a component
preventing degeneration and/or decomposition of an injectable formulation, that is, is
added to prevent decomposition of animal/vegetable organic substances by activity of
microorganisms. The preservative must be harmless to a human body and efficacy and/
or toxicity of an active ingredient must not be varied or altered by adding the
preservative.
[16] Preservatives used for a water-soluble injectable formulation as a major type of in
jections may include, for example; phenol, m-cresol, benzyl alcohol, methyl paraben,
propyl paraben, penzalkonium chloride, thiomerosal, chlorobutanol, phenoxyethanol,
and so forth. However, in the case where a non-aqueous oily injectable formulation
according to the present invention includes a preservative normally used for a watersoluble
injectable formulation, it is difficult to attain preservative efficacy substantially
equal to that of the water-soluble injectable formulation.
[17] The lipophilic preservative useable in the present invention may be at least one
selected from a group consisting of, for example; phenol, m-cresol, benzyl alcohol,
methyl paraben, propyl paraben, penzalkonium chloride, thiomerosal, chlorobutanol,
ethanol, phenoxyethanol and phenoxyethanol, without being particularly limited
thereto.
[18] A content of the lipophilic preservative may range from 0.01 to 20% (w/v) in relation
to a total weight of the formulation. In the case where the content is too low, it is
difficult to attain preservative effects. On the contrary, if the content is too high, toxic
effects may be exhibited, thus not being preferable. More preferably, the content
ranges from 0.1 to 10% (w/v) and, most preferably, 0.1 to 5% (w/v).
[19] A hydrophilic excipient used herein means an excipient combined with the lipophilic
preservative and enabling contact between a water phase, in which microorganisms are
present, and the lipophilic preservative. Practical examples of the hydrophilic excipient
may be at least one selected from a group consisting of; propyleneglycol,
polyethyleneglycol, polypropyleneglycol, glycerol, acetic acid, citric acid, dimethylsulfoxide
(DMSO), N-methylpyrrolidone (NMP) and dimethylacertamide (DMA),
without being particularly limited thereto.
[20] Propyleneglycol as a hydrophilic excipient is an excipient generally used as a cosolvent
for increasing drug solubility in an aqueous solution type formulation and/or an
emulsion formulation. Propyleneglycol also known to have preservative efficacy may
be used as a disinfectant. However, in order to use propyleneglycol as a preservative
component of the aqueous solution type injectable formulation, this must be applied at
high concentration. Therefore, it is known that propyleneglycol has a difficulty in use
as a typical preservative in an injectable formulation for directly administering a drug
solution to blood, subcutaneous tissue, skin or muscle. However, according to the
present invention, it was surprisingly identified that, even adding a small amount of
porpyleneglycol together with a lipophilic preservative to a non-aqueous injectable for
mulation, preservative efficacy of the formulation may be enhanced.
[21] As other examples of the hydrophilic excipient, polyethyleneglycol may have a
number average molecular weight ranging from 200 to 10,000,000 while polypropy
leneglycol may have a number average molecular weight of 200 to 5,000.
[22] A content of the foregoing hydrophilic excipient may range from 0.01 to 20% (w/v)
in relation to a total weight of the formulation. In the case where the content is too low,
it is difficult to attain synergic effects of preservative efficacy. On the contrary, if the
content is too high, toxic effects may be exhibited or phase separation may occur, thus
not being preferable. More preferably, the content ranges from 0.1 to 10% (w/v) and,
particularly preferably, 0.1 to 5.0% (w/v).
[23] The injectable formulation of the present invention may have high preservative
efficacy. In general, microorganisms may barely survive in a non-aqueous oily for
mulation with lack of water, that is, in a low water activity state. However, in the case
where the injectable formulation is introduced together with trace of water surrounding
microorganisms, some may occasionally survive depending upon types of the mi
croorganisms. Specifically, S. aureus, A. niger, P. aeruginosa, C. albicans, or the like,
seldom die but maintain a constant number of individuals or extremely slowly die.
[24] In view of characteristics of an injectable formulation for direct administration of a
drug solution into blood, subcutaneous tissue, skin or muscle, the injectable for
mulation needs higher preservative efficacy, than a level at which microorganisms are
not grown and which is substantially not satisfactory for use.
[25] Accordingly, the present invention is characterized in that a lipophilic preservative
may be in contact with a water phase containing microorganisms introduced therein by
combining the lipophilic preservative with a hydrophilic excipient, thus attaining
excellent preservative efficacy, compared to using the lipophilic preservative alone.
More particularly, preservative efficacy of the injectable formulation according to the
present invention (abbrev. to 'inventive formulation') may mean that, when adding 105
to 106 bacteria to 1ml or 1 g of the inventive formulation, the number of bacteria is
reduced to 103 to 104 or less after 6 hours. Otherwise, the preservative efficacy may
mean that, when 105 to 106 bacteria are added to 1 ml or 1 g of the inventive for
mulation, the number of bacteria is reduced to 104 to 105 or less after 7 days. In this
regard, the bacteria may be S. aureus, P. aeruginosa, E. coli, etc., without being p ar
ticularly limited thereto.
[26] As the preservative efficacy attained by the present invention is expressed with
reference to fungi, it may mean that the number of fungi is reduced to 105 or 106 or less
after 7 days when 105 to 106 fungi are added to 1mg or 1 g of the inventive for
mulation. Otherwise, the foregoing may mean that the number of fungi is reduced to 10
to 104 or less after 7 days when 105 to 106 fungi are added to 1 mg or 1 g of the
inventive formulation. In this case, such fungi may be A. niger, C. albicans, etc.,
without being particularly limited thereto.
[27] In this regard, a partition coefficient '' of partition between a non-aqueous oil phase
and a water phase containing microorganisms therein, may become a criterion to
determine preservative efficacy. The partition coefficient P is a value calculated by
dividing a concentration of preservative in the oil phase by a concentration of
preservative in the water phase. If the partition coefficient is high, the concentration of
preservative in the oil phase is increased, thus causing a difficulty in attaining
preservative effects. In contrast, if the partition coefficient is low, distribution between
the oil phase and the water phase may be improved, thus expecting sufficient
preservative effects even in the water phase. Accordingly, the lower the partition co
efficient, the higher the preservative efficacy of the oil formulation to bacteria or fungi
living in the water phase may be considered.
[28] Such a partition coefficient may be considerably varied depend upon kinds of oil
and/or preservative. For instance, in the case where the partition coefficient is
measured by using medium chain triglyceride (MCT) as oil and phenol as a
preservative, which is most frequently used in the art, the measured partition co
efficient may be about 13.7, in turn being 1.1 in respects to Log P. This means that a
concentration of phenol present in the water phase is only 1/13.7 of a concentration of
phenol present in the oil phase, thus causing a difficulty in attaining desired
preservative efficacy.
[29] For a formulation that does not contain a hydrophilic excipient used in the present
invention, since the partition coefficient is very high, a concentration of the lipophilic
preservative in the water phase is considerably decreased. In contrast, the formulation
containing the hydrophilic excipient shows increased concentration in the water phase.
[30] A multi-dose type non-aqueous oily injectable formulation according to the present
invention may include a lipophilic preservative and a hydrophilic excipient, both of
which have different affinities to oil, and exhibit non-phase separation of the hy
drophilic excipient from the oil.
[31] Phase separation occurring between the lipophilic preservative and the hydrophilic
excipient may be partially varied depending upon kinds of materials used for com
bination of the foregoing substances and contents thereof. The reason for this is
presumed that inherent characteristics of individual components in a specific com
bination of the lipophilic preservative and the hydrophilic excipient may mutually
influence one another. Accordingly, based on overall description of the present
invention as described above, there is no difficulty to suitably determine contents and
content ratios of non-phase separable lipophilic preservative and hydrophilic excipient
by those skilled in the related art, through repeated experimentation of selected
substances. Although one embodiment of the foregoing is proposed as Comparative
Example 1 below, the scope of the present invention is not particularly limited thereto.
[32] According to one preferred embodiment, a content ratio of a lipophilic preservative
and a hydrophilic excipient may be slightly varied depending upon types of materials
used. However, generally considering expression of improved preservative efficacy,
inhibition of phase separation, or the like, the content ratio may range from 1:10 to
10: 1 in terms of ratio by weight.
[33] According to an exemplary embodiment, an injectable formulation of the present
invention may be a formulation comprising; 0.1 to 100 mg/ml of hGH, 0.1 to 1.5% w/v
of propyleneglycol and 0.1 to 1% w/v of phenol suspended in a medium chain
triglyceride (MCT).
[34] Of course, a non-aqueous oily injectable formulation according to the present
invention may further include other components known in the related art.
Advantageous Effects of Invention
[35] A non-aqueous oily injectable formulation according to the present invention does
not show phase separation, is stable, and exhibits very high preservative efficacy. Con
sequently, the inventive formulation may be effectively used as an injectable for
mulation, specifically, a multi-dose type non-aqueous oily injectable formulation.
Mode for the Invention
[36] Hereinafter, preferred embodiments of the present invention will be described in
detail by the following examples, however, the scope of the present invention is not
particularly limited to such examples.
[37] With reference to The European Pharmacopoeia and The US Pharmacopoeia, a
method of assaying preservative efficacy was executed while focusing on S. aureus
and A. niger with strong survival characteristics, among a variety of bacteria and fungi.
[38] Experiments to identify whether typical preservatives used for medication exhibit
preservative efficacy refer to preservative efficacy tests (PETs). Such a PET is to
determine a variation in number of individuals of microorganisms over time, after
adding the microorganisms to a formulation containing the preservative to reach 105 to
106 per 1ml or 1 g of the formulation. PETs are representatively stated in The
European Pharmacopeia (EP 5.1.3 Efficacy of Antimicrobial Preservation) and The US
Pharmacopoeia (USP 5 1 Antimicrobial Effectiveness Testing).
[39] The present invention will be better understood from the following examples and
comparative examples.
[40] Comparative Example 1: Test for measurement of phase stability by
preservative
[41] An experiment was executed to identify whether a formulation is separated into an
oil phase and a water phase in the case where the formulation is stored at 5°C, as a pre
determined storage condition, for several days. Results of the experiment are shown in
Table 1 below. In the following table, the content was expressed in units of % by
weight (w/v).
[42] Table 1
[Table 1]
Phase stability along with preservative
Preservative Propyleneglycol Phase separation
Phenol/propyleneglycol 0.3% phenol 0.9% propy Non-phase
composite formulation leneglycol separation
0.3% phenol 1% propy Phase separation
leneglycol
Ethanol/propyleneglycol 1% ethanol 1% propy Non-phase
composite formulation leneglycol separation
1% ethanol 2% propy Phase separation
leneglycol
Benzyl alcohol/ 1.5% benzyl 1% propy Non-phase
propyleneglycol composite alcohol leneglycol separation
formulation 1.5% benzyl 1.5% propy Phase separation
alcohol leneglycol
[43] As shown in the above Table 1, phase separation was varied depending upon concen
trations of propyleneglycol and the preservative, thus demonstrating that the consti
tutional composition at which phase separation occurred is not suitable for an in
jectable formulation.
[44] Comparative Example 2 : Preservative efficacy b addition of hydrophobic
preservative to non-aqueous oily formulation
[45] In this present experiment, preservative efficacy of a preservative was assayed in the
case where a preservative such as phenol, cresol, benzyl alcohol, chlorobutanol, etc.,
commonly available in injectable formulations, was used alone in MCT oil.
[46] More particularly, after dissolving a preservative in MCT as non-aqueous oil, a
preservation test was executed under the conditions listed in Table 2 below, according
to test methods in The European Pharmacopoeia ('') and/or The US Pharmacopoeia
('USP'). Measurement of the number of microorganisms during the preservation test
was conducted by a membrane filtration method. More particularly, lxlO 5 to lxlO 6
CFU/mL of each strain was added to a sample to reach 1% (v/v), followed by flowing
the sample through a 0.45/ cellulose nitrate filter. The filter was washed three times,
using 100 mL of a sodium chloride-peptone buffer (pH 7.0). For bacteria culture, the
filter was moved to Trypticase soy agar. On the other hand, for culturing fungi, the
filter was moved to Sabouraud dextrose agar. The bacteria were cultured at 30 to 35°C
while the fungi were cultured at 20 to 25°C, respectively, for 5 days. From the r e
spective cultured products, strains were counted and Log reduction values thereof were
estimated. In order to appropriately conduct the filtering and dilution, a solution
prepared by dissolving a surfactant, that is, polysorbate 80 in a saline solution to a con
centration of 10% was used as a dilute solution at initial dilution. The dilute solution
was then diluted 1000 times to obtain a uniform solution. Additional dilution was im
plemented using a saline solution to be diluted by 10 fold. Hereinafter, the preservation
tests in the following examples have been executed according to the present test
procedures, unless otherwise stated.
[47] Test results are shown respectively in Tables 3 and 4 below.
[48] Table 2
[Table 2]
Formulation containing preservative only added to MCT oil
Table 3
[Table 3]
Preservative efficacy of formulation containing preservative only added to MCT oil (S.
aureus)
[50] Table 4
[Table 4]
Preservative efficacy of formulation containing preservative only added to MCT oil (A.
niger)
[51] As shown in the above Tables 3 and 4, for both S. aureus and A. niger, a formulation
containing a preservative added thereto did not impart noticeable variation, as
compared to a formulation without a preservative. Such results demonstrate that the
lipophilic preservatives such as phenol, cresol, benzyl alcohol, chlorobutanol, etc., did
not sufficiently function as the preservative in the MCT oil as a non-aqueous solution.
[52] Example 1: Effect of propyleneglycol PG in non-aqueous oily formulation
[53] The present experiment was executed to identify effects of a formulation comprising
a mixture of a hydrophobic preservative and a hydrophilic excipient.
[54] As shown in Table 5 below, propyleneglycol was suitably mixed with ethanol,
phenol and benzyl alcohol to prepare a formulation. Although propyleneglycol itself is
immiscible with MCT oil, this may be miscible with MCT if mixed with phenol,
benzyl alcohol, ethanol, etc. in an appropriate relative ratio. Considering influence of
temperature, the mixing ratio may be determined by selecting two individual for
mulations having appropriate constitutional compositions at which the foregoing two
formulations can be mixed well while not becoming cloudy (or turbid) even though the
prepared formulation is stored at 5°C for several days.
[55] The foregoing formulations were subjected to preservation tests and test results
thereof are shown in Tables 6 and 7.
[56] Table 5
[Table 5]
Formulation containing propyleneglycol as well as preservative added to MCT oil
Table 6
[Table 6]
Preservative efficacy of formulation containing propyleneglycol as well as preservative
added to MCT oil (S. aureus)
[58] N/R: No recover
Table 7
[Table 7]
Preservative efficacy of formulation containing propyleneglycol as well as preservative
added to MCT oil (A. niger)
[60] N/R: No recover
[61] As identified from the above Tables 6 and 7, the formulation comprising propy
leneglycol mixed with ethanol, phenol and/or benzyl alcohol exhibited very high
preservative efficacy. The reason for this is considered to be because propyleneglycol
moves into a microorganism phase and maintains a very high concentration in a microenvironment,
thereby expressing preservative efficacy of propyleneglycol itself.
Moreover, it is presumed that, as a concentration of propyleneglycol is increased, an
increase in osmotic pressure in the micro-environment and, in addition, an increase in
concentration (of the preservative) due to variation in a partition coefficient, may also
influence the foregoing results.
[62] Example 2 : Preservative efficacy of other hydrophilic excipients in non-aqueous
oily formulation
[63] The present experiment was executed according to the same procedures as described
in Example 1, except that propyleneglycol was replaced with polyethylenegly col (PEG
300) and polypropyleneglycol (PPG 400) (see Table 8 below).
[64] Results thereof are shown in Tables 9 and 10 below.
[65] Table 8
[Table 8]
Formulation containing preservative and PEG300 or the like added to MCT oil
Formulation No. Oil Additive (%(w/v))
9 MCT 1% polyethyleneglycol(PEG 300) + 0.5% phenol
10 MCT 1% polyethyleneglycol(PEG 300) + 1.5% benzyl
alcohol
1 1 MCT 1% polyethyleneglycol(PEG 300) + 2% ethanol
12 MCT 5% polypropyleneglycol(PPG 400) + 0.5% phenol
[66] Table 9
[Table 9]
Preservative efficacy of formulation containing preservative and PEG300 or the like
added to MCT oil (S. aureus)
[67] N/R: No recover
[68] Table 10
[Table 10]
Preservative efficacy of formulation containing preservative and PEG300 or the like
added to MCT oil (A. niger)
[69] N/R: No recover
[70] As confirmed from results in the above Tables 9 and 10, formulations comprising
poly ethylenegly col mixed with ethanol, phenol, benzyl alcohol, etc., as well as a for
mulation comprising polypropyleneglycol mixed with phenol, exhibited very high
preservative efficacy. Like propyleneglycol described in Example 1, the reason for the
foregoing is considered that, as a concentration of a co-solvent is increased in the
micro-environment, osmotic pressure is increase and, in addition, a concentration (of
the preservative) around microorganisms is increased due to variation in partition co
efficient.
[71] Example 3 : Preservative efficacy in slow release type human growth hormone
contained in non-aqueous oil
[72] The present experiment was executed to test preservative efficacy of an extendedrelease
(or slow release) type formulation containing human growth hormone
(SR-hGH) which was prepared by spray drying and suspended in MCT to reach 100
mg/ml in terms of a powder form.
[73] More particularly, Tween 80 as a surfactant was added in an amount of 0.01 wt. , in
relation to a total weight of a buffer solution, to 5 mM of a phosphate buffer solution
containing human growth hormone dissolved with a concentration of 2 mg/ml therein.
2 mg/ml of sodium hyaluronate having a molecular weight of 1,000,000 was dissolved
in the foregoing solution to prepare a final solution. The final solution was fed at a
flow rate of 3 ml/min into a spray dryer (Buchi 190), thus forming microfine particles.
In this regard, a temperature of dried air flowing into the spray dryer was 85°C while
the formed microfine particles had an average particle diameter of 3 . 5 g of the
sodium hyaluronate microfine particles containing human growth hormone was
dispersed in 500 ml of ethanol containing lecithin dissolved with a concentration of 10
mg/ml therein to thus obtain a dispersion. The dispersion was fed into a spray dryer
(Buchi 190), thereby forming microfine particles coated with lecithin and having an
average particle diameter of 7 . In this case, the kinds of additives used herein and
contents thereof are shown in Table 11 below.
[74] Table 1 1
[Table 11]
SR-hGH suspension formulation
[75] Based on the foregoing description, tests were executed upon a variety of mi
croorganisms and results thereof are shown in Tables 12 to 16 below.
[76] Table 12
[Table 12]
Preservative efficacy of SR-hGH suspension formulation (S. aureus)
[79]
[80]
[81] N/R: No recover
[82] Table 15
[Table 15]
Preservative efficacy of SR-hGH suspension formulation (A. niger)
[83]
[84]
[85] N/R: No recover
[86] From the above Tables 12 to 16, it can be seen that formulations comprising propy
leneglycol mixed with preservatives (Formulations 14 to 16) exhibited excellent
preservative efficacy, compared to the formulation without containing a preservative
(Formulation 13).
[87] Example 4 : Preservative efficacy in oil other than MCT
[88] The present experiment was executed to identify whether a preservative system
developed according to the present invention may be applied to oils other than MCT.
Sesame oil and peanut oil, respectively, were mixed with propyleneglycol and phenol
to prepare formulations, in turn forming SR-hGH suspensions, as described in
Example 3. Preservative efficacy of each of the obtained suspensions was compared to
formulations without preservatives. In this case, the kinds of oils used herein and
contents of additives are shown in Table 17 below.
[89] Table 17
[Table 17]
Formulation containing other oil as a substitute for MCT
[90] Table 18
[Table 18]
Preservative efficacy of formulation containing other oil as a substitute for MCT (S.
aureus)
[91] As shown in the above Table 18, it was confirmed that the preservative composed of
phenol and propyleneglycol, which are mixed with MCT in previous example also
exhibits excellent preservative efficacy in sesame oil and peanut oil, respectively, as
non-aqueous solutions other than MCT.
[92] Example 5 : Preservative efficacy along with concentration of propyleneglycol
[93] In the present example, formulations were prepared by fixing a concentration of
phenol as a lipophilic preservative to 0.3% while varying a concentration of propy
leneglycol in the range of less than 1%, as shown in Table 19 below. For the prepared
formulations, preservation tests were executed and results thereof are shown in Table
20 below.
[94] Table 19
[Table 19]
SR-HGH suspension formulation with varied concentrations of propyleneglycol
therein
[95] Table 20
[Table 20]
SR-HGH suspension formulation with varied concentrations of propyleneglycol
therein
[96] As shown in the above Table 20, it can be seen that excellent preservative efficacy is
exhibited in the range of concentration of the propylenelycol of less than 1%.
[97] Example 6 : Measurement of content of preservative in water phase
[98] A formulation was prepared by adding phenol alone to MCT oil to reach 0.5%, while
another formulation was prepared by further adding polypropyleneglycol (PPG 400) to
reach 5%. Then, after feeding oil and a saline solution in a ratio of 19:1 to the for
mulation and sufficiently mixing the same, an amount of phenol contained in each
phase was quantified through HPLC to calculate a partition coefficient. Results thereof
are shown in Table 2 1 below.
[99] Table 2 1
[Table 21]
Variation in partition coefficient by addition of polypropyleneglycol
[100] Partition coefficient (P) = phenol concentration of oil phase/phenol concentration of
saline phase
[101] As shown in the above Table 21, the formulation without polypropyleneglycol
showed too high a partition coefficient, thus having a very low phenol concentration in
a saline phase. On the contrary, the formulation containing polypropyleneglycol
exhibited a relatively high concentration of polypropyleneglycol in the saline phase. As
a result, it can be seen that a concentration of phenol, that is, the preservative, in the
saline phase is increased, thus increasing preservative efficacy of the oily formulation.
[102] As set forth above, a variety of modifications and applications will be possibly made
by those skilled in the art to which the present invention pertains, within the scope of
the present invention.
Claims
An injectable formulation, comprising:
a physiologically effective amount of active ingredient;
oil containing the active ingredient;
a hydrophilic excipient non-phase separable from the oil; and
an lipophilic preservative combined with the hydrophilic excipient,
which exhibits higher preservative efficacy, compared to administration
of the lipophilic preservative alone.
The formulation according to claim 1, wherein the preservative efficacy
is expressed by 103 to 104 or less of bacteria after 6 hours when adding
105 to 106 bacteria to 1ml or 1 g of the injectable formulation.
The formulation according to claim 1, wherein the preservative efficacy
is expressed by 104 to 105 or less of bacteria after 7 days when adding
105 to 106 bacteria to 1ml or 1 g of the injectable formulation.
The formulation according to claim 2 or 3, wherein the bacteria are S.
aureus, P aeruginosa or E. coli.
The formulation according to claim 4, wherein the bacteria are S.
aureus.
The formulation according to claim 1, wherein the preservative efficacy
is expressed by 105 to 106 or less of fungi after 7 days when adding 105
to 106 fungi to 1ml or 1 g of the injectable formulation.
The formulation according to claim 1, wherein the preservative efficacy
is expressed by 103 to 104 or less of fungi after 7 days when adding 105
to 106 fungi to 1ml or 1 g of the injectable formulation.
The formulation according to claim 6 or 7, wherein the fungi are A.
niger or C. albicans.
The formulation according to claim 8, wherein the fungi are A. niger.
The formulation according to claim 1, wherein the active ingredient is a
protein or peptide drug and hyaluronic acid or an inorganic salt thereof.
The formulation according to claim 1, wherein the oil is at least one or
two or more selected from a group consisting of; monoglyceride,
diglyceride, triglyceride, medium chain triglyceride (MCT), sesame oil,
Arachis oil (peanut oil), castor oil, olive oil, corn oil, cotton seed oil,
soybean oil, peppermint oil, coconut oil, palm seed oil and Safflower
oil.
The formulation according to claim 1, wherein the lipophilic
preservative is at least one selected from a group consisting of; phenol,
m-cresol, benzyl alcohol, methyl paraben, propyl paraben, penzalkonium
chloride, thiomerosal, chlorobutanol, ethanol and phenoxyethanol.
The formulation according to claim 1, wherein the hydrophilic
excipient is at least one selected from a group consisting of; propy
leneglycol, polyethyleneglycol, polypropyleneglyocl, glycerol, acetic
acid, citric acid, dimethylsulfoxide (DMSO), N-methylpyrrolidone
(NMP) and dimethylacetamide (DMA).
The formulation according to claim 1, wherein the lipophilic
preservative has a concentration of 0.01 to 20% weight/volume (%
(w/v)), while the hydrophilic excipient has a concentration of 0.01 to
20% weight/volume (% (w/v)).
The formulation according to claim 1, wherein a ratio by weight of the
lipophilic preservative to the hydrophilic excipient ranges from 1:10 to
10:1.
The formulation according to claim 1, wherein the injectable for
mulation is a formulation for multi-dose administration.
The formulation according to claim 1, wherein 0.1 to 100 mg/ml of
hGH, 0.1 to 1.5% weight/volume (% (w/v)) of propyleneglycol and 0.1
to 1% weight/volume (% (w/v)) of phenol are suspended in MCT.