CN106794149A - The oral administration compound formulation of ester containing omega-3 fatty acid and Statins - Google Patents
The oral administration compound formulation of ester containing omega-3 fatty acid and Statins Download PDFInfo
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- CN106794149A CN106794149A CN201580055280.9A CN201580055280A CN106794149A CN 106794149 A CN106794149 A CN 106794149A CN 201580055280 A CN201580055280 A CN 201580055280A CN 106794149 A CN106794149 A CN 106794149A
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- compound formulation
- oral administration
- statins
- administration compound
- fatty acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
Abstract
The present invention relates to the medicine compound preparation comprising omega-3 fatty acid ester and Statins.Oral administration compound formulation of the present invention includes the tablet containing Statins, it is encapsulated in the capsule comprising omega-3 fatty acid ester, and therefore preparation blocks external environment condition, such as water, low pH etc. completely in principle, and have the advantages that to show stability high, disintegration rate and dissolution rate excellent.
Description
Technical field
The present invention relates to the compound formulation containing omega-fatty acid and Statins.
Background technology
Omega-fatty acid serum triglyceride (TG) level of reduction, contraction and diastolic blood pressure and pulse frequency and blood coagulation because
Worked in the activity of sub- VII- phosphatide complexes, and without any side effect.
Known statins by about 1/3rd of the risk reduction of coronary heart disease (CHD) to its original level, but it
Only there is limited effect to TG and serum high-density LP (HDL).
Therefore, the advantage of the compound formulation containing HMG-CoA reductase inhibitor and omega-fatty acid is that they can
Effectively to reduce cholesterol and triglycerides in the hypercholesterolemiapatients patients blood for needing control triglyceride levels simultaneously
Level.In this regard, various trials have been carried out to preparing the compound formulation containing two kinds of medicines.
For example, Korean Patent Publication No 10-2012-0109950 (document 1) describe containing omega-fatty acid and
The oral complex composition and its method of HMG-CoA reductase inhibitor, in addition, 2) Korean Patent Publication No 10-2013-
0104059 (document 2) discloses a kind of medicine compound preparation, and it contains omega-fatty acid internal layer, waterborne polymeric intermediate layer, with
And the outer layer of HMG-CoA reductase inhibitor or its pharmaceutically acceptable salt.
Additionally, U.S. Patent Application Publication No. No. 2013-0115281 (document 3) discloses multiphase soft gelatin preparation, wherein
Soft gelatin formulation comprising the solid dosage forms containing pretreatment statin compound and the soft gelatin system containing omega-fatty acid
Agent is adhered to mutually.
However, Statins is uniformly coated on the outer layer containing ω -3 in the preparation that is related to of the invention disclosed in document 1 and 2
On.Therefore, compared with conventional tablet, these preparations have very big surface area, therefore, these preparations can because of with external rings
Border (such as moisture, low pH) interacts and causes stability and content to reduce and cause the impurity to increase.Therefore, statin is controlled
The dissolution pattern of class is extremely difficult, and is likely to there is problem in terms of content uniformity is maintained.
In the invention situation disclosed in document 3, it is also the preparation that Statins can interact with outside moisture, from
And cause stability and content reduction and the increased problem of impurity.
In this case, the present inventor makes great efforts the compound formulation that exploitation is wherein mixed with Statins and ω -3, as a result, he
Develop the preparation that can overcome foregoing invention shortcoming, so as to complete the present invention.
Disclosure
Technical problem
It is an object of the present invention to provide a kind of compound formulation containing omega-fatty acid and Statins, it has excellent
Different stability, can suppress the increase of impurity, and can prevent the decline of statins content.
It is a further object to provide a kind of compound formulation containing omega-fatty acid and Statins, it has
Excellent disintegration rate and dissolution rate.
Technical scheme
On the one hand, the invention provides a kind of compound formulation for being administered orally, including：
Capsule containing omega-fatty acid；With
Tablet containing Statins, it is encapsulated in the capsule.
In above-mentioned compound formulation, the tablet containing Statins can also contain disintegrant, and the tablet containing Statins can
Be with film coating matrix coat tablet.
In an exemplary embodiment, the shell of the capsule can be made up of at least one selected from following component：
Gum arabic, bassora gum, karaya, Indian gum, guar gum, locust bean gum, tara gum, konjac glucomannan, phycocolloid, agar, card
Drawing glue,Pectin,Mannosan, glycerine, gelatin and xanthans.
In another exemplary embodiment, the preparation can be the compound formulation for being administered orally, wherein
Under conditions of common paddle method, the Statins that compound formulation is included is compound relative to described in the stripping quantity in -1 hour 30 minutes
The gross weight of preparation is 70wt%-85wt%；Or under conditions of basket method, the Statins that compound formulation is included was in 30 minutes -1
Stripping quantity in hour is 70wt%-85wt% relative to the gross weight of the compound formulation.
Beneficial effects of the present invention
Oral administration compound formulation of the invention includes the capsule containing omega-fatty acid and comprising being encapsulated in the capsule
In the tablet containing Statins, and the tablet containing Statins isolates with external environment condition (such as water, low pH etc.) completely.Cause
This, oral administration compound formulation of the invention has the advantages that to show high stability, excellent disintegration rate and dissolution rate.
Additionally, although the tablet containing statins is encapsulated in capsule, oral administration compound formulation of the present invention according to
So show disintegration high and rate of dissolution.Additionally, the compound formulation for oral administration of the invention is in suitable time range
Interior disintegration and dissolution, therefore Statins can avoid exposure to hydrochloric acid in gastric juice.
Further, since the shell of capsule is transparent, so the tablet of the statin being included in is with the naked eye can from outside
See, therefore, compound formulation of the invention has psychology and demonstration effect etc. by trusting customer.
BRIEF explanation
Fig. 1 illustrates the excellent dissolution rate of oral administration compound formulation of the present invention.
Fig. 2 illustrates the image of the oral administration compound formulation of the preparation of the embodiment of the present invention 1.
Preferred forms
Hereinafter present invention will be described in detail.
The present invention relates to a kind of oral administration compound formulation, it includes the capsule containing omega-fatty acid；Be encapsulated in
The tablet containing Statins in the capsule, and in an exemplary embodiment, the compound formulation can be that medicine is combined
Preparation.
As used herein, term " capsule " refers to be filled into capsule or by the shape in capsule by by medicament or medicine
The material prepared into encapsulation, term " tablet " refers to that medicament or medicine are compressed into specific shape after additive is added
Shape and the material for preparing.
Omega-fatty acid can serum triglyceride (TG) level of reduction, reduce shrink and diastolic blood pressure and pulse frequency with
And worked in the activity of reduction proconvertin-phosphatide complexes, almost it is free from side effects in human body.
As used herein, term " omega-fatty acid " is referred to as omega-3 unsaturated fatty acid, ω -3 height not including all
Those of saturated fatty acid and polyunsaturated fatty acid (PUFA), also including DHA (DHA), eicosapentaenoic acid
(EPA), arachidonic acid (ARA), clupanodonic acid, alpha-linolenic acid, its mixture etc..In an exemplary
In, omega-fatty acid can be omega-fatty acid Arrcostab.
Statins can postpone cholesterol by suppressing HMG-CoA reductase (the cholesterol generating rate in its control volume)
Produce or removed by improving liver and be already present on the ability of low-density lipoprotein (LDL) cholesterol in blood and reduce blood
Cholesterol levels in liquid.That is, the Main Function of Statins is to reduce LDL-C level.
Known statins by about 1/3rd of the risk reduction of coronary heart disease (CHD) to its original level, but it
To TG and serum high-density LP (HDL) only have limited effect.
Patient LDL and the TG level of hypercholesterolemia and combination dyslipidemia rise, it will therefore be apparent that working as
When LDL and TG levels are all high, it can be effective to co-administer omega-fatty acid and Statins.
Therefore, the oral administration compound formulation of joint omega-fatty acid and Statins is not only expected and can provide as above
Described excellent effect, and expect that it solves patient and needs to take two kinds of inconvenience of different pharmaceutical, therefore with improvement medicine
The advantage of compliance.
However, the compound formulation comprising two or more active components may have a problem that：Two or more medicines
Thing can be reacted with each other, and dissolution, the disintegration of fractions etc. are likely to become the problem of other compositions, therefore will stay in body
These compositions of interior application are made preparation and are not easy to for those of ordinary skills.
For example, in compound formulation, wherein the preparation comprising omega-fatty acid is present in the core of compound formulation
Near, and Statins is then arranged on the surface of core, when human body is applied to, it is necessary to required Statins is coated in
The surface of core, therefore compared with general tablet, generate very big surface area.
In this area, it is commonly known that due to external environment condition (moisture, due to containing CO2The low pH that causes of air etc.) cause him
The unstability of spit of fland class.Due to the factor of external environment condition, when the area of Statins and air contact becomes big, in fact it could happen that such as
The problems such as stability and the reduction of Statins content, impurity increase.Due to above-mentioned problem, without the approval of corresponding authoritative institution
In the case of can not enter commercial market medicine may face such problem, i.e., they can not industrially be applicable.
In addition, in above-mentioned preparation, when Statins is arranged on the surface of core, it is extremely difficult to control dissolution pattern,
And probably gone wrong in terms of the homogeneity of content.Therefore, many experiments of those of ordinary skill in the art and mistake
It is by mistake inevitable for completing this preparation, therefore increased the cost of its exploitation.
Furthermore, it is possible to consider multiphase soft gelatin preparation, the soft gelatin formulation of such as attachment mutually (including contain Statins
Solid pharmaceutical preparation) and soft gelatin formulation (containing omega-fatty acid).
Even if in this case, Statins is still within the same terms interacted with outside moisture and air,
Therefore Statins stability and content reduction can not be solved the problems, such as and increases impurity.
In compound formulation of the invention, the structure that preparation has is：Tablet containing Statins is encapsulated (being incorporated into
It is internal) in the capsule containing omega-fatty acid.The inside of capsule is encapsulated in due to tablet, and outside moisture and air can not
By with lipophilic characteristics capsule containing omega-fatty acid layer, thus intercepted in principle contained Statins in tablet with it is all
Such as moisture, the contact of air external environment condition, therefore, Statins can have long-term stability.
In an exemplary embodiment of the present invention, compound formulation includes the capsule containing omega-fatty acid；And bag
Tablet containing the Statins (such as Atorvastatin or Rosuvastatin) being encapsulated in the capsule, it is chronically at various temperature
Under damp condition.Result finds that Statins content contained in compound formulation is not changed in, it is therefore evident that compound formulation
Excellent stability.
In another exemplary embodiment, compound formulation includes the capsule containing omega-fatty acid；And comprising
The tablet of the Statins (such as Atorvastatin or Rosuvastatin) being encapsulated in capsule, is carried out dissolution test, as a result
It was found that the capsule was disintegrated completely in 30 minutes.
In addition, when the compound formulation is carried out into dissolution test (basket method or common paddle method), finding relative to compound system
The Statins that the gross weight of agent about 70wt% to about 85wt% is measured is in dissolution in 30 minutes to 1 hour.In an exemplary implementation
In scheme, during dissolution test, relative to the Statins that the gross weight about 70wt% to about 85wt% of compound formulation is measured,
Under conditions of 50rpm to 150rpm, in dissolution in 30 minutes to 1 hour.
That is, because compound formulation is disintegrated and/or dissolution in suitable time range, thus can prevent due to
It is extremely fast disintegration and/or dissolution and by Statins be exposed to hydrochloric acid in gastric juice.
Additionally, the structure of oral administration compound formulation of the present invention is for omega-fatty acid and Statins (i.e. active component)
Internal effect there is no any negative interaction, and show its effect.
In an exemplary embodiment, it is preferable that the omega-fatty acid in oral administration compound formulation of the present invention
Content relative to oral compound formulation gross weight, be 30wt% to 80wt%.
When the content of omega-fatty acid is less than 30wt% relative to the gross weight for the compound formulation that is administered orally, deposit
In the shortcoming that therapeutic effect is not enough.Conversely, when the content of omega-fatty acid is relative to for the total of the compound formulation that is administered orally
When weight is higher than 80wt%, prepared soft capsule size will increase, so as to reduce drug compliance.
In an exemplary of the invention, the content phase of Statins in oral administration compound formulation of the present invention
Gross weight for oral administration compound formulation is preferably 0.5wt% to 10wt%.
When the content of statins is less than 0.5wt% relative to the gross weight of oral administration compound formulation, exists and control
The not enough shortcoming of therapeutic effect.Conversely, when the content of Statins is higher than 10wt% relative to the gross weight of oral administration compound formulation
When, due to the excess of medicine, it may occur however that side effect.
Contained Statins is selected from following at least one in oral administration compound formulation of the invention：Atorvastatin,
Rosuvastatin, Lovastatin, Simvastatin, Pravastatin, Fluvastatin and its pharmaceutically acceptable salt.
As used herein, term " pharmaceutically acceptable salt " refers to be prepared by conventional method of the art
Salt, and it is technology known to persons of ordinary skill in the art to prepare the method for pharmaceutically acceptable salt.
Specifically, the pharmaceutically acceptable salt may include pharmaceutically or raw derived from following inorganic acid and organic acid
Acceptable salt in Neo-Confucianism, but pharmaceutically acceptable salt not limited to this.
The example of suitable acid can include：Hydrochloric acid, bromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid,
Glycolic, lactic acid, salicylic acid, butanedioic acid, p-methyl benzenesulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid, benzoic acid, third
Diacid, naphthalene-2-sulfonic acid, benzene sulfonic acid etc..
The salt as derived from suitable alkali may include the salt of alkali metal (such as sodium or potassium) and alkaline-earth metal (such as magnesium).
Tablet containing Statins of the invention can be the form of the thin membrane coated tablet coated with film coating matrix, described
Film coating matrix can include at least one being selected from the group：Hydroxypropyl cellulose, hydroxypropyl cellulose methylcellulose, second
Base cellulose and polyvinyl acetate.In an exemplary embodiment, the film coating matrix to be used can include Europe
Bar generation (Opadry), it includesIn vain,Powder,Green,Tangerine,Blue,Yellow,Palm fibre etc..
As described above, when the oral administration compound formulation comprising Statins and omega-fatty acid is prepared, two kinds of medicines
Between interaction may cause problem.Therefore, the structure of oral administration compound formulation of the present invention is：Piece containing Statins
Agent is enclosed in the capsule containing omega-fatty acid, therefore, it can block the interaction between two kinds of medicines.
Oral administration compound formulation containing statins may include pharmaceutically acceptable excipient, adhesive, collapse
Solution agent, disintegration accelerator, lubricant, film coating agent, film coating matrix, enteric film coated substrate, soft capsule matrix, flexible glue
Capsule suspending agent etc..
Especially, the disintegrant can include at least one being selected from the group：Hydroxypropyl methyl cellulose, corn form sediment
Powder, agar powder, methylcellulose, bentonite, hydroxypropul starch, sodium carboxymethylcellulose, sodium alginate, carboxymethylcellulose calcium
Calcium, calcium citrate, NaLS, silicic acid anhydride, glucan, ion exchange resin, polyvinyl acetate, formaldehyde, junket egg
In vain, amylose, guar gum, sodium acid carbonate, polyvinylpyrrolidone, calcium phosphate, gelling starches, gum arabic, side chain
Starch, pectin, polyphosphate sodium, ethyl cellulose, white sugar, aluminium-magnesium silicate, D-glucitol, Crospovidone, DST, cross-linked carboxymethyl
Sodium cellulosate and sodium starch glycollate.In an exemplary embodiment, the disintegrant be preferably selected from it is following at least
It is a kind of：Crospovidone, DST, Ac-Di-Sol and sodium starch glycollate.
In order to improve the disintegration rate of oral administration compound formulation of the invention, disintegrant can be excessively used.It is excessively
Refer to the amount relative to the gross weight containing Statins tablet more than 20wt%.
Generally, when using excessive disintegrant, tablet may be dissolved with faster speed, and presence may suck sky
Moisture in gas is so as to influence the possibility of tablet stability.However, in the case of oral administration compound formulation of the invention,
Tablet containing Statins is encapsulated in the capsule containing omega-fatty acid, even if therefore using excessive disintegrant, piece
The stability of agent is unaffected, because compound formulation prevents moisture.
In oral administration compound formulation of the invention, wherein the shell or shell membrane of the capsule containing omega-fatty acid can be with
Constituted comprising or by least one component being selected from the group：Arabic gum, bassora gum, Karaya Gum, Indian gum, guar gum, Chinese scholartree
Bean gum, tara gum, konjac glucomannan, algin, agar, carrageenan,Pectin,Mannosan, glycerine,
Gelatin and xanthans.In an exemplary embodiment, described shell can be concentration glycerine or gelatin (for example,)。
Shell on capsule, can determine the species and its amount of component so that be included in glue in the level of routine techniques
Medicine such as omega-fatty acid inside softgel shell can be decomposed and dissolved with appropriate velocity interval.
The present invention is described in detail
Hereinafter, the present invention will be described in more detail with reference to following examples.However, these embodiments are only used
In descriptive purpose, and the present invention is not restricted by the embodiments.
The preparation 1 of the oral administration compound formulation of the present invention of embodiment 1.
<The preparation of the thin membrane coated tablet containing Atorvastatin>
Composition according to table 1 below, by Atorvastatin calcium, microcrystalline cellulose, Lactose hydrate and calcium carbonate in mixing
Mix in device, with adhesive solution (polysorbate80, hydroxypropyl cellulose) mixing, pelletized in speed mixer-granulator,
Stirred 8 hours at 50 DEG C, ground in granulator is ground, by being added thereto to Ac-Di-Sol and stearic acid
Magnesium, the mixed processing after, and use rotary pelleting machine compressing tablet.Then, polyvinyl acetate (PVA) and water are mixed to prepare bag
Clothing solution, and tablet is coated with Coating Solution, and dry to prepare the film coating tablet containing Atorvastatin.
<The encapsulating of the film coating tablet comprising Atorvastatin and the formation of soft capsule>
Then, soft capsule shell is prepared using carrageenan and concentration glycerine by soft capsule thin film fabrication machine, and will be contained
The film coating tablet for having Atorvastatin is encapsulated in capsule, injects omega-fatty acid, and seal using soft gelatin encapsulation machine
Close.
[table 1]
The preparation 2 of the oral administration compound formulation of the present invention of embodiment 2.
It is prepared using the identical mode of embodiment 1, difference is to be replaced with 6mg hydroxypropyl methyl celluloses (HPMC)
Polyvinyl acetate in the tablet coating portion of table 1.
The preparation 3 of the oral administration compound formulation of the present invention of embodiment 3.
Composition according to table 2 below, by Atorvastatin calcium, microcrystalline cellulose, Lactose hydrate, calcium carbonate and crosslinking carboxylic
Sodium carboxymethylcellulose pyce (7.5mg) mixes in a mixer, mixes with adhesive solution (polysorbate80, hydroxypropyl cellulose),
Pelletized in speed mixer-granulator, dried 8 hours at 50 DEG C, ground in granulator is ground, by being added thereto to hand over
Connection sodium carboxymethylcellulose (7.5mg) and magnesium stearate, the mixed processing after, and use rotary pelleting machine compressing tablet.Then, by hydroxyl
Propyl methocel (HPMC) and water mixing are coated tablet with Coating Solution, and dry to prepare with preparing Coating Solution
Film coating tablet containing Atorvastatin.Then, carry out comprising the thin of Atorvastatin in the same manner as example 1
Encapsulating and soft capsule the formation treatment of film-coated tablet.
[table 2]
The preparation 4 of the oral administration compound formulation of the present invention of embodiment 4.
It is prepared by the way of same as Example 3, difference is by the tablet portion containing Statins in table 2
The amount of Lactose hydrate reduce to 36.5mg, and the amount of Ac-Di-Sol is increased into 30mg.By cross-linked carboxymethyl
Sodium cellulosate is divided into two parts, and is added with after mixing before combination respectively.
The preparation 5 of the oral administration compound formulation of the present invention of embodiment 5.
It is prepared by the way of same as Example 4, difference is the mistake in mixing Atorvastatin and excipient
15mg disintegrants (DST) is further added in journey and the amount of Lactose hydrate is reduced to 21.5mg.
The preparation 6 of the oral administration compound formulation of the present invention of embodiment 6.
<The preparation of the coating tablet containing Atorvastatin>
Composition according to table 3 below, by Atorvastatin calcium, calcium carbonate, pregelatinized starch and microcrystalline cellulose mixed
Mix in clutch, mix with adhesive solution (polyoxyethylene sorbitan monoleate, hydroxypropyl cellulose), pelletized in speed mixer-granulator,
Dried 8 hours at 50 DEG C, ground in granulator is ground, by adding Ac-Di-Sol, sodium starch glycolate, hard
Fatty acid magnesium and cataloid carry out rear mixed processing, and use rotary pelleting machine compressing tablet.Then, willIn vain
(OY-C-7000A) tablet is coated with Coating Solution with preparing Coating Solution with water mixing, and drying contains atropic to prepare
Cut down the film coating tablet of statin.
<The encapsulating of the coated tablet comprising Atorvastatin and the formation of capsule>
Then, soft capsule shell is prepared using gelatin and concentration glycerine by soft capsule thin film fabrication machine, and will contain Ah
The film coating tablet of atorvastatin is encapsulated in capsule, injection omega-fatty acid ethyl ester 90, and uses soft gelatin encapsulation machine
Closing.
[table 3]
The preparation 7 of the oral administration compound formulation of the present invention of embodiment 7.
<The preparation of the coating tablet containing Rosuvastatin>
Composition according to table 4 below, rosuvastain calcium and calcium phosphate dibasic anhydrous are mixed in a mixer, and micro-
Crystalline cellulose, Lactose hydrate and PVPP mixing, by adding magnesium stearate (from palm oil extract) after at mixing
Reason, and use rotary pelleting machine compressing tablet.Then, mixPowder (03F640026), second alcohol and water are molten to prepare coating
Liquid, and tablet Coating Solution is coated and dries to prepare the tablet containing Rosuvastatin.
<The encapsulating of the coated tablet comprising Rosuvastatin and the formation of capsule>
Then, soft capsule shell is prepared using gelatin and concentration glycerine by soft capsule thin film fabrication machine, and will be containing auspicious
The easypro film coating tablet for cutting down statin is encapsulated in capsule, injection omega-fatty acid ethyl ester 90, and uses soft gelatin encapsulation machine
Closing.
[table 4]
The preparation of film coating tablet of the comparative example 1. containing Atorvastatin
Formula according to the tablet portion containing Statins and tablet coating portion (omits the coating comprising Atorvastatin
The encapsulating of tablet and the formation of capsule) prepare Atorvastatin film coating tablet.
The preparation of the compound formulation of comparative example 2., wherein the plain piece containing Statins is encapsulated in and contains omega-fatty acid
Pharmaceutical preparation in
Compound formulation is prepared using with the identical mode of embodiment 1 described in table 1, difference is in eliminating embodiment 1
Method for coating film (be free of tablet coating portion).
The commercially available Atorvastatin single medicine tablet of comparative example 3.
Marketed tablet (the Lipitor containing Atorvastatin calcium as active component is bought from commercial market Pfizer (South Korea) pharmaceutical Co. Ltd (Pfizer Pharmaceuticals Korea Ltd.)) and be used as
Comparative example 3.
The preparation of the compound formulation of comparative example 4., wherein containing ω -3 by being encapsulated in without disintegrant tablet containing Statins
In the pharmaceutical preparation of fatty acid ester
Prepare compound formulation by the way of same as Example 2, difference is not comprising crosslinking carboxylic first in the preparation
Base sodium cellulosate, and the content of Lactose hydrate increases to 66.5mg.
The preparation of film coating tablet of the comparative example 5. containing Rosuvastatin
Formula according to the tablet portion containing Statins and tablet coating portion (omits the coating containing Rosuvastatin
The encapsulating of tablet and the formation of capsule) prepare the coated tablet containing Rosuvastatin.
The stability test of EXPERIMENTAL EXAMPLE 1. (accelerated test)
The sample that will be prepared in embodiment 1 and 2 and comparative example 1 and 2 is in 40 ± 2 DEG C and 75 ± 5% relative humidity (RH)
Under conditions of store, and the amount of Atorvastatin calcium in each sample is calculated behind 0,1,2,3 and 6 months.Result is shown in down
In table 5.The sample of comparative example 1 and 2 shows the significant reduction of the amount of Atorvastatin calcium when Storage period was by two months, and
Sample from embodiment 1 and 2 even displays that the amount of Atorvastatin calcium has almost no change after storing 6 months.Also
It is to say, even if the compound formulation prepared in embodiment 1 and 2 still shows excellent stability after long term storage.
[table 5]
The stability test of EXPERIMENTAL EXAMPLE 2. (long term test)
The sample that will be prepared in embodiment 1 and 2 and comparative example 1 and 2 is in 25 ± 2 DEG C and the bar of 60 ± 5%RH
Stored under part, and the amount of Atorvastatin calcium in each sample is calculated behind 0,2,4,6,8,12 and 18 months.Result is shown
In table 6 below.The sample of comparative example 1 and 2 shows the significant drop of the amount of Atorvastatin calcium when 4 months shelf lifes have been crossed
It is low, and the sample from embodiment 1 and 2 even displays that the amount of Atorvastatin calcium has almost no change after storing 6 months.
Even if that is, the compound formulation prepared in embodiment 1 and 2 still shows excellent stability after long term storage.
[table 6]
The stability test of EXPERIMENTAL EXAMPLE 3. (long term test)
The sample that will be prepared in embodiment 3 and comparative example 3 is in room temperature (20 ± 2 DEG C) and the condition of 60 ± 5%RH
Lower storage, and calculate the amount of 0,1 and the Atorvastatin calcium after 3 months in each sample.Result is shown in table 7 below.It is included in reality
Apply the tablet containing Atorvastatin in the soft capsule of example 3 and the single tablet phase containing Atorvastatin in comparative example 3
Than showing similar stability.
[table 7]
The stability test of EXPERIMENTAL EXAMPLE 4. (long term test)
The sample prepared in embodiment 3 and comparative example 3 is stored under conditions of 45 ± 2 DEG C and 75 ± 5%RH, and
Calculate 0,1 and after 3 months in each sample Atorvastatin calcium amount.Result is shown in table 8 below.It is included in the flexible glue of embodiment 3
The tablet containing Atorvastatin in capsule shows similar compared with single tablet of the comparative example 3 containing Atorvastatin
Stability.
[table 8]
The stability test of EXPERIMENTAL EXAMPLE 5. (long term test)
The sample that will be prepared in embodiment 7 and comparative example 5 is in room temperature (20 ± 2 DEG C) and the condition of 60 ± 5%RH
Lower storage, and calculate the amount of 0,1 and the rosuvastain calcium after 3 months in each sample.Result is shown in table 9 below.It is included in reality
Apply the tablet containing Rosuvastatin in the soft capsule of example 7 and the single tablet containing Atorvastatin in comparative example 5
Compared to showing similar stability.
[table 9]
The stability test of EXPERIMENTAL EXAMPLE 6. (long term test)
The sample prepared in embodiment 7 and comparative example 5 is stored under conditions of 45 ± 2 DEG C and 75 ± 5%RH, and
Calculate 0,1 and after 3 months in each sample rosuvastain calcium amount.Result is shown in table 10 below.It is included in the flexible glue of embodiment 7
The tablet containing Rosuvastatin in capsule shows class compared with the single tablet containing Atorvastatin in comparative example 5
As stability.
[table 10]
The dissolution test of EXPERIMENTAL EXAMPLE 7. (1)
The second dissolution test method (common oar method) according to Pharmacopoeia Coreana, determines embodiment under the conditions of tests below
3rd, 4 and 5 and comparative example 3 and 4 in prepare sample in Atorvastatin calcium dissolution rate.Result is as shown in Figure 1.
Leaching condition：
1. dissolution solution：Water
2. dissolution liquor capacity：900mL
RPM：50rpm
The slaking test of EXPERIMENTAL EXAMPLE 8. (1)
Based on the slaking test in Pharmacopoeia Coreana ordinary test method, measurement is implemented in 37 DEG C of the aqueous solution (pH1.2)
The disintegration time of the tablet prepared in the compound formulation prepared in example 1 and 7 and comparative example 1 and 5.
As a result, the tablet prepared in the compound formulation for being prepared in embodiment 1 and 7 and comparative example 1 and 5 was at about 30 minutes
Inside it is disintegrated completely.That is, although the tablet containing Statins is encapsulated in the inside of compound formulation, the capsule of embodiment exists
It is disintegrated completely in 30 minutes, is then discharged to the outside omega-fatty acid, so as to confirms their excellent disintegratives.
The dissolution test of EXPERIMENTAL EXAMPLE 9. (2)
First method (basket method) and second method (common paddle method) according to Pharmacopoeia Coreana dissolving-out method, in following test bars
The dissolution rate of prepared sample in embodiment 1 (Atorvastatin calcium) and embodiment 7 (rosuvastain calcium) is measured under part.
As a result, when being tested under 150rpm according to first method (basket method), what is prepared in embodiment 1 and 7 is compound
Display has the Statins meltage (gross weight based on compound formulation) of about 70wt% to 85wt% to preparation in 1 hour.
In addition, when being tested at 100 rpm according to second method (common paddle method), the compound formulation prepared in embodiment 1 and 7
Display has the Statins meltage (gross weight based on compound formulation) of about 70wt% to 85wt% in 1 hour.
Claims (12)
1. a kind of oral administration compound formulation, comprising：
Capsule containing omega-fatty acid；With
Tablet containing Statins, it is encapsulated in the capsule.
2. oral administration compound formulation as claimed in claim 1, it is characterised in that the Statins be selected from the group at least
It is a kind of：Atorvastatin, Rosuvastatin, Lovastatin, Simvastatin, Pravastatin, Fluvastatin and its can pharmaceutically connect
The salt received.
3. oral administration compound formulation as claimed in claim 1, it is characterised in that the tablet containing Statins also contains
Disintegrant.
4. oral administration compound formulation as claimed in claim 3, it is characterised in that the disintegrant be selected from the group at least
It is a kind of：Hydroxypropyl methyl cellulose, cornstarch, agar powder, methylcellulose, bentonite, hydroxypropul starch, carboxymethyl cellulose
Plain sodium, sodium alginate, calcium carboxymethylcellulose, calcium citrate, NaLS, silicic acid anhydride, glucan, amberlite
It is fat, polyvinyl acetate, formaldehyde, casein, amylose, guar gum, sodium acid carbonate, polyvinylpyrrolidone, calcium phosphate, solidifying
Gelling starch, gum arabic, amylopectin, pectin, polyphosphate sodium, ethyl cellulose, white sugar, aluminium-magnesium silicate, D-glucitol,
Crospovidone, DST, Ac-Di-Sol and sodium starch glycollate.
5. oral administration compound formulation as claimed in claim 3, it is characterised in that during wherein described disintegrant is selected from the group
It is at least one：Crospovidone, DST, Ac-Di-Sol and sodium starch glycollate.
6. oral administration compound formulation as claimed in claim 1, it is characterised in that the content of omega-fatty acid is relative to mouth
Compound formulation gross weight is taken for 30wt% to 80wt%.
7. oral administration compound formulation as claimed in claim 1, it is characterised in that the content of Statins is compound relative to oral
Total formulation weight is 0.5wt% to 10wt%.
8. oral administration compound formulation as claimed in claim 1, it is characterised in that the tablet containing Statins is by film
Coated substrate is coated.
9. oral administration compound formulation as claimed in claim 3, it is characterised in that what the film coating matrix was selected from the group
It is at least one：Hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose and polyvinyl acetate.
10. oral administration compound formulation as claimed in claim 1, it is characterised in that the shell of the capsule by be selected from the group to
A kind of few component is constituted：Arabic gum, bassora gum, Karaya Gum, Indian gum, guar gum, locust bean gum, tara gum, konjac glucomannan,
Algin, agar, carrageenan,Pectin,Mannosan, glycerine, gelatin and xanthans.
11. oral administration compound formulations as claimed in claim 1, it is characterised in that described multiple under conditions of common paddle method
Close the Statins that is included of preparation is in the gross weight of the relatively described compound formulation of amount of institute's dissolution in -1 hour 30 minutes
70wt%-85wt%.
12. oral administration compound formulations as claimed in claim 1, it is characterised in that under conditions of basket method, compound formulation institute
Comprising Statins in institute's dissolution in -1 hour 30 minutes the relatively described compound formulation of amount gross weight be 70wt%-
85wt%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210667299.0A CN115025060A (en) | 2014-08-13 | 2015-08-13 | Oral administration compound preparation containing omega-3 fatty acid ester and statins |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2014-0105463 | 2014-08-13 | ||
| KR20140105463 | 2014-08-13 | ||
| PCT/KR2015/008523 WO2016024844A1 (en) | 2014-08-13 | 2015-08-13 | Oral combined preparation containing omega-3 fatty ester and statin-based drug |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210667299.0A Division CN115025060A (en) | 2014-08-13 | 2015-08-13 | Oral administration compound preparation containing omega-3 fatty acid ester and statins |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106794149A true CN106794149A (en) | 2017-05-31 |
Family
ID=55304389
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210667299.0A Pending CN115025060A (en) | 2014-08-13 | 2015-08-13 | Oral administration compound preparation containing omega-3 fatty acid ester and statins |
| CN201580055280.9A Pending CN106794149A (en) | 2014-08-13 | 2015-08-13 | The oral administration compound formulation of ester containing omega-3 fatty acid and Statins |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210667299.0A Pending CN115025060A (en) | 2014-08-13 | 2015-08-13 | Oral administration compound preparation containing omega-3 fatty acid ester and statins |
Country Status (4)
| Country | Link |
|---|---|
| KR (1) | KR101752700B1 (en) |
| CN (2) | CN115025060A (en) |
| PH (1) | PH12017500269A1 (en) |
| WO (1) | WO2016024844A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101950907B1 (en) * | 2016-02-05 | 2019-02-21 | 한국유나이티드제약 주식회사 | Oral preparation comprising liphophilic drug and a oilproof material coated solid formulation |
| WO2017171484A1 (en) * | 2016-03-31 | 2017-10-05 | 한미약품 주식회사 | Composite preparation for oral administration containing omega-3 fatty acid or ester thereof, and hydroxymethyl glutaryl coenzyme a reductase inhibitor |
| KR102240935B1 (en) | 2019-06-04 | 2021-04-15 | (주) 노바렉스 | Techniques for improving the disintegration and storage stability of tablet containing fingerroot extract as an active ingredient |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130115281A1 (en) * | 2010-06-03 | 2013-05-09 | Accucaps Industries Limited | Pharmaceutical formulations of statins and omega-3 fatty acids for encapsulation |
| US20130136792A1 (en) * | 2010-06-03 | 2013-05-30 | Accucaps Industries Limited | Multi phase soft gel capsules, apparatus and method thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MX2012003555A (en) * | 2009-09-23 | 2012-07-03 | Amarin Corp Plc | Pharmaceutical composition comprising omega-3 fatty acid and hydroxy-derivative of a statin and methods of using same. |
| KR101466617B1 (en) * | 2011-11-17 | 2014-11-28 | 한미약품 주식회사 | ORAL COMPLEX FORMULATION COMPRISING OMEGA-3 FATTY ACID AND HMG-CoA REDUCTASE INHIBITOR WITH IMPROVED STABILITY |
| KR20130104059A (en) * | 2012-03-12 | 2013-09-25 | 주식회사 드림파마 | Pharmaceutical complex formulation for oral administration for treatment of hyperlipidenmia |
| TW201347754A (en) * | 2012-05-07 | 2013-12-01 | Omthera Pharmaceuticals Inc | Compositions of statins and omega-3 fatty acids |
-
2015
- 2015-08-13 KR KR1020157022218A patent/KR101752700B1/en active IP Right Grant
- 2015-08-13 CN CN202210667299.0A patent/CN115025060A/en active Pending
- 2015-08-13 WO PCT/KR2015/008523 patent/WO2016024844A1/en active Application Filing
- 2015-08-13 CN CN201580055280.9A patent/CN106794149A/en active Pending
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2017
- 2017-02-13 PH PH12017500269A patent/PH12017500269A1/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130115281A1 (en) * | 2010-06-03 | 2013-05-09 | Accucaps Industries Limited | Pharmaceutical formulations of statins and omega-3 fatty acids for encapsulation |
| US20130136792A1 (en) * | 2010-06-03 | 2013-05-30 | Accucaps Industries Limited | Multi phase soft gel capsules, apparatus and method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| KR101752700B1 (en) | 2017-07-03 |
| PH12017500269B1 (en) | 2017-07-03 |
| PH12017500269A1 (en) | 2017-07-03 |
| CN115025060A (en) | 2022-09-09 |
| KR20160030383A (en) | 2016-03-17 |
| WO2016024844A1 (en) | 2016-02-18 |
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