CN107802629B - A kind of purposes of pharmaceutical composition in treatment of atherosclerosis drug is prepared - Google Patents
A kind of purposes of pharmaceutical composition in treatment of atherosclerosis drug is prepared Download PDFInfo
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- CN107802629B CN107802629B CN201711388345.9A CN201711388345A CN107802629B CN 107802629 B CN107802629 B CN 107802629B CN 201711388345 A CN201711388345 A CN 201711388345A CN 107802629 B CN107802629 B CN 107802629B
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- miltefosine
- sodium ferulate
- cyclodextrin
- pharmaceutical composition
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
Abstract
The invention belongs to field of medicaments, purposes of more particularly to a kind of pharmaceutical composition in treatment of atherosclerosis drug is prepared.Described pharmaceutical composition is made of pharmaceutically acceptable pharmaceutic adjuvant, sodium ferulate and Miltefosine；The weight part ratio of sodium ferulate and Miltefosine is in described pharmaceutical composition：21~32 parts by weight of sodium ferulate, 20~28 parts by weight of Miltefosine；Described pharmaceutical composition is oral solid formulation；The human body of described pharmaceutical composition is administered daily dosage and is calculated as 1.58~2.40mg/kg weight with Miltefosine.The composition of sodium ferulate and Miltefosine has good therapeutic effect to atherosclerosis.
Description
Technical field
The invention belongs to field of medicaments, and in particular to a kind of pharmaceutical composition is in treatment of atherosclerosis drug is prepared
Purposes.
Background technology
Atherosclerosis (Atherosclerosis, AS) is fat under artery and its arterial wall inner membrance and inner membrance of branch
Matter is calm, while travels to hyperplasia under inner membrance with medial smooth muscle cells, makes intimal thickening, forms yellow or lark shape
Such as a kind of common vascular diseases of atheromatous plaque.The disease often involves the heart, brain, kidney, and related to the diseases such as diabetes, hypertension.
It is now recognized that the deposition of arterial wall endothelial injuries and lipid is the startup factor of atherosclerosis.In addition, in recent years
The research come is, it was also found that inflammatory factor takes part in the occurrence and development of atherosclerosis, and inflammation hypothesis can be to artery congee
The pathomechanism of sample hardening, which is made, more fully, reasonably to be explained.Certain lipid materials such as lysophosphatide, oxygen sterol in blood
Deng as signaling molecule, after being combined with cell receptor can activated gene expression, induce a variety of promotion inflammatory cytokines and height occur
Expression.This process is considered taking part in the development of atherosclerosis.Inflammation process marker such as C reactive proteins, adherency point
Son, inflammatory mediator（Such as TNF-α, IFN-γ）Have proved to be the sensitive Testing index of atherosclerosis（Chu Xianming, Lee
Ice, An Yi, Dong fruit hero inflammation and relationship between atherosclerosis progress《Chinese molecular cardiology magazine》 ,
2010 , 11 (3) :184-188）.
It is typically low fat diet cooperation drug therapy to the treatment of atherosclerosis at present, common drug includes drop blood
Fat drug：Such as Statins, fibrates, niacin, cholestyramine, clofibrate；Unrighted acid such as yishouning, lipid level and heart arteries and veins pleasure
Deng；Sodium alginate；Antiplatelet and anticoagulation medicine：Such as aspirin, clopidogrel, hirudin.But said medicine is equal
Increased in the presence of more apparent adverse reaction such as lesions of liver and kidney or bleeding risk etc..
Invention content
For the above-mentioned prior art, it is controlled the object of the present invention is to provide a kind of pharmaceutical composition in preparation atherosclerosis
Treat the purposes in drug.To achieve the above object, the technical solution adopted by the present invention is as follows：
A kind of purposes of pharmaceutical composition in treatment of atherosclerosis drug is prepared, described pharmaceutical composition is by medicine
Acceptable pharmaceutic adjuvant, sodium ferulate and Miltefosine are made on；Sodium ferulate and rice replace good fortune in described pharmaceutical composition
New weight part ratio is：21~32 parts by weight of sodium ferulate, 20~28 parts by weight of Miltefosine；Described pharmaceutical composition is oral
Solid pharmaceutical preparation.
Preferably, the weight part ratio of sodium ferulate and Miltefosine is in described pharmaceutical composition：22 weight of sodium ferulate
Part, 27 parts by weight of Miltefosine.
Preferably, the weight part ratio of sodium ferulate and Miltefosine is in described pharmaceutical composition：26 weight of sodium ferulate
Part, 25 parts by weight of Miltefosine.
Preferably, the weight part ratio of sodium ferulate and Miltefosine is in described pharmaceutical composition：31 weight of sodium ferulate
Part, 22 parts by weight of Miltefosine.
Preferably, the human body of described pharmaceutical composition is administered daily dosage and is calculated as 1.58~2.39mg/ with Miltefosine
Kg weight, preferably 1.587~2.381 mg/kg weight.
Preferably, above-mentioned oral solid formulation is granule.
Preferably, the pharmaceutic adjuvant of above-mentioned granule is by beta-cyclodextrin, gamma-cyclodextrin, microcrystalline cellulose, low-substituted hydroxypropyl
Cellulose, PVP K30 and water composition.
Preferably, beta-cyclodextrin dosage is 0.6 times of sodium ferulate weight in above-mentioned granule, and gamma-cyclodextrin dosage is
0.4 times of sodium ferulate weight, microcrystalline cellulose dosage are 1 times of sodium ferulate weight, and low-substituted hydroxypropyl cellulose dosage is
0.17 times of sodium ferulate weight, PVP K30 dosage are 0.17 times of sodium ferulate weight.
Preferably, above-mentioned granule is prepared via a method which：
The first step：Take recipe quantity sodium ferulate, Miltefosine, beta-cyclodextrin, gamma-cyclodextrin, microcrystalline cellulose, low substitution
The sieve of 80 mesh excessively is spare respectively for hydroxypropylcellulose, PVP K30, and PVP K30 is taken to add water that the water that mass percentage concentration is 4% is made
Solution for standby；
Second step：Recipe quantity beta-cyclodextrin, gamma-cyclodextrin mixing are taken, the water for adding in 6 times of weight of beta-cyclodextrin is ground into paste
Shape is added in colloid mill, adds in recipe quantity sodium ferulate and Miltefosine, is ground 45 minutes, is spray-dried cyclodextrin encapsulated
Composition granule；
Third walks：Cyclodextrin encapsulated composition granule obtained by second step is taken to cross 60 mesh sieve, recipe quantity microcrystalline cellulose is added in, low takes
It is mixed for hydroxypropylcellulose, adds in first step gained PVP K30 aqueous solution, prepare softwood, cross 30 mesh wet sieving diameters and pelletize, wet
18 mesh sieve whole grain is crossed after grain is dry in 60 DEG C, is distributed into aluminium plastic bag to obtain the final product.
Sodium ferulate described in technical solution of the present invention, the entitled Sodium ferulate of English, No. CAS is 24276-84-
4, it is the sodium salt of ferulic acid, wherein ferulic acid is widely present in plurality of Chinese and natural plants, and with anti-oxidant, anti-inflammatory etc.
Activity.
Miltefosine described in technical solution of the present invention, English entitled Miltefosine, No. CAS is 58066-85-6, mesh
It is preceding to have gone through listing for treating visceral leishmaniasis, cutaneous Leishmaniasis and the mucous membrane leishmaniasis of 12 years old or more patient.
Beta-cyclodextrin described in technical solution of the present invention acts on starch for ring dextrin glucosyl transferase and generates
The cyclic oligosaccharide that is combined with α-Isosorbide-5-Nitrae-glycosidic bond of 7 glucose, belong to common medicinal supplementary material, standard is recorded in middle traditional Chinese medicines
Allusion quotation version four in 2015.
Gamma-cyclodextrin described in technical solution of the present invention belongs to common medicinal supplementary material, and standard is recorded in United States Pharmacopeia
USP35。
Microcrystalline cellulose described in technical solution of the present invention is alpha-cellulose made from the fiber pulp of cellulosic plant,
Part depolymerization under the action of inorganic acid is purified and is obtained.Belong to common medicinal supplementary material, as filler and disintegrant etc., standard
It is recorded in Chinese Pharmacopoeia version four in 2015.
Low-substituted hydroxypropyl cellulose described in technical solution of the present invention is low substitution 2- hydroxypropyl ether celluloses, is commonly used for collapsing
Agent and filler etc. are solved, standard is recorded in Chinese Pharmacopoeia version four in 2015.
PVP K30 described in technical solution of the present invention generates vinyl pyrrole under elevated pressure for pyrrolidones and ethylene
Alkanone monomer, the 1 vinyl 2 pyrrolidone homopolymer polymerizeing under catalyst action, belongs to common medicinal supplementary material,
As binder and cosolvent etc., standard is recorded in Chinese Pharmacopoeia version four in 2015.
Above-mentioned sodium ferulate, Miltefosine, beta-cyclodextrin, gamma-cyclodextrin, microcrystalline cellulose, low-substituted hydroxypropyl cellulose,
There is sale in PVP K30 market.
The present inventor shows that sodium ferulate there is certain treatment to imitate atherosclerosis by experimental study
Fruit.Miltefosine does not have treatment of atherosclerosis effect, in the presence of the trend for aggravating atherosclerosis during exclusive use；With
When sodium ferulate is used in combination, then there is synergistic effect to the study of anti-atherogenic effect of sodium ferulate.Sodium ferulate and rice
There is good therapeutic effect to atherosclerosis for the new composition of good fortune.
Specific embodiment
The present invention is further explained with reference to embodiment.It should be understood that following embodiment is only used for solving
It releases the present invention rather than limits the scope of the invention.
Embodiment 1 treats granule and its preparation of atherosclerosis
Auxiliary material：Beta-cyclodextrin, gamma-cyclodextrin, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, PVP K30 and water.β-
Cyclodextrin dosage is 0.6 times of sodium ferulate weight, and gamma-cyclodextrin dosage is 0.4 times of sodium ferulate weight, microcrystalline cellulose
Dosage is 1 times of sodium ferulate weight, and low-substituted hydroxypropyl cellulose dosage is 0.17 times of sodium ferulate weight, PVP K30
Dosage is 0.17 times of sodium ferulate weight.
Preparation method：
The first step：Take recipe quantity sodium ferulate, Miltefosine, beta-cyclodextrin, gamma-cyclodextrin, microcrystalline cellulose, low substitution
The sieve of 80 mesh excessively is spare respectively for hydroxypropylcellulose, PVP K30, and PVP K30 is taken to add water that the water that mass percentage concentration is 4% is made
Solution for standby；
Second step：Recipe quantity beta-cyclodextrin, gamma-cyclodextrin mixing are taken, the water for adding in 6 times of weight of beta-cyclodextrin is ground into paste
Shape is added in colloid mill, adds in recipe quantity sodium ferulate and Miltefosine, is ground 45 minutes, is spray-dried to obtain ring
Cyclodextrin inclusion compound particle；
Third walks：Cyclodextrin encapsulated composition granule obtained by second step is taken to cross 60 mesh sieve, recipe quantity microcrystalline cellulose is added in, low takes
It is mixed for hydroxypropylcellulose, adds in first step gained PVP K30 aqueous solution, prepare softwood, cross 30 mesh wet sieving diameters and pelletize, wet
18 mesh sieve whole grain is crossed after grain is dry in 60 DEG C, is distributed into aluminium plastic bag to obtain the final product.
Embodiment 2 treats granule and its preparation of atherosclerosis
Auxiliary material：Beta-cyclodextrin, gamma-cyclodextrin, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, PVP K30 and water.β-
Cyclodextrin dosage is 0.6 times of sodium ferulate weight, and gamma-cyclodextrin dosage is 0.4 times of sodium ferulate weight, microcrystalline cellulose
Dosage is 1 times of sodium ferulate weight, and low-substituted hydroxypropyl cellulose dosage is 0.17 times of sodium ferulate weight, PVP K30
Dosage is 0.17 times of sodium ferulate weight.
Preparation method：
The first step：Take recipe quantity sodium ferulate, Miltefosine, beta-cyclodextrin, gamma-cyclodextrin, microcrystalline cellulose, low substitution
The sieve of 80 mesh excessively is spare respectively for hydroxypropylcellulose, PVP K30, and PVP K30 is taken to add water that the water that mass percentage concentration is 4% is made
Solution for standby；
Second step：Recipe quantity beta-cyclodextrin, gamma-cyclodextrin mixing are taken, the water for adding in 6 times of weight of beta-cyclodextrin is ground into paste
Shape is added in colloid mill, adds in recipe quantity sodium ferulate and Miltefosine, is ground 45 minutes, is spray-dried to obtain ring
Cyclodextrin inclusion compound particle；
Third walks：Cyclodextrin encapsulated composition granule obtained by second step is taken to cross 60 mesh sieve, recipe quantity microcrystalline cellulose is added in, low takes
It is mixed for hydroxypropylcellulose, adds in first step gained PVP K30 aqueous solution, prepare softwood, cross 30 mesh wet sieving diameters and pelletize, wet
18 mesh sieve whole grain is crossed after grain is dry in 60 DEG C, is distributed into aluminium plastic bag to obtain the final product.
Embodiment 3 treats granule and its preparation of atherosclerosis
Auxiliary material：Beta-cyclodextrin, gamma-cyclodextrin, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, PVP K30 and water.β-
Cyclodextrin dosage is 0.6 times of sodium ferulate weight, and gamma-cyclodextrin dosage is 0.4 times of sodium ferulate weight, microcrystalline cellulose
Dosage is 1 times of sodium ferulate weight, and low-substituted hydroxypropyl cellulose dosage is 0.17 times of sodium ferulate weight, PVP K30
Dosage is 0.17 times of sodium ferulate weight.
Preparation method：
The first step：Take recipe quantity sodium ferulate, Miltefosine, beta-cyclodextrin, gamma-cyclodextrin, microcrystalline cellulose, low substitution
The sieve of 80 mesh excessively is spare respectively for hydroxypropylcellulose, PVP K30, and PVP K30 is taken to add water that the water that mass percentage concentration is 4% is made
Solution for standby；
Second step：Recipe quantity beta-cyclodextrin, gamma-cyclodextrin mixing are taken, the water for adding in 6 times of weight of beta-cyclodextrin is ground into paste
Shape is added in colloid mill, adds in recipe quantity sodium ferulate and Miltefosine, is ground 45 minutes, is spray-dried to obtain ring
Cyclodextrin inclusion compound particle；
Third walks：Cyclodextrin encapsulated composition granule obtained by second step is taken to cross 60 mesh sieve, recipe quantity microcrystalline cellulose is added in, low takes
It is mixed for hydroxypropylcellulose, adds in first step gained PVP K30 aqueous solution, prepare softwood, cross 30 mesh wet sieving diameters and pelletize, wet
18 mesh sieve whole grain is crossed after grain is dry in 60 DEG C, is distributed into aluminium plastic bag to obtain the final product.
The antiatherosclerotic effect of 4 pharmaceutical composition of embodiment learns experiment
SPF grades of male SD rats, 180~220g of weight, purchased from Shandong University's Experimental Animal Center.Rat is fitted after buying
Answering property is raised one week, water of freely ingesting, and feeds Rat Standard daily ration-type feed（Meet U.S.'s NIH41 standards；Purchased from Henan day
It speeds experimental animal feed corporation,Ltd）.
Adaptability raising terminates, and changes and feeds high lipid food（Formula：1% cholesterol, 0. 2% bovine bile, 10% lard, 10% yolk
Powder, 78. 8% basal feeds；Pull together feed corporation,Ltd purchased from Beijing Australia of section）.High lipid food feeds first day every rat abdomen
600,000 U/kg of chamber injection vitamine D3.Immunologic mjury was carried out to rat in 2nd day:Oralbumin is with physiological saline solution system
Into the solution of 1mg/ml, isometric oralbumin normal saline solution and Sigma-F5881 Freund's complete adjuvant mixings are taken
Antigen liquid is made.In the subcutaneous multi-point injection antigen liquid of rat back, every rat injection dosage is calculated as 3 with oralbumin
mg/kg.After finishing 3 weeks with oralbumin normal saline solution challenge is injected intraperitoneally in antigen liquid injection again, often
Week 1 time, each dosage is calculated as 2.5 mg/kg with oralbumin, excites 5 times altogether.24 hours after last excitation, randomly select
5 rats, cervical dislocation are put to death, and remove overall length artery along aorta petal to common iliac artery bifurcation, physiological saline is cleaned, 4% first
Aldehyde solution is fixed, and graded ethanol dehydration, paraffin embedding cuts 4 μm of thin slices, hematoxylin eosin staining.Pathology is carried out under microscope
Each layer lesion of artery is observed in histological examination, observes the Atheromatosis such as the accumulation of foam cells stove or atheromatous plaque
Change is considered as modeling success.
Modeling success rat 60 is taken, is randomly divided into 6 groups, every group 10.
Each group animal administration prescription see the table below.Table middle dosage and volume are the dosage and volume of single-dose.Administration way
Diameter is gastric infusion, and administration frequency is administered 4 weeks altogether to be administered daily 1 time.It freely ingests water, feeds Rat Standard daily ration-type
Feed（Meet U.S.'s NIH41 standards；Purchased from Henan Tian Chi experimental animals feed corporation,Ltd）.
I.e. first group is model group；Second to the 4th group be experimental drug group, prescription respectively with of embodiment 1 to 3
Raw material prescription proportioning is identical in granula；Five, the six groups are respectively that sodium ferulate, Miltefosine are administered alone group.
In above-mentioned each group, the rat of Miltefosine is administered daily dosage and is calculated as 10~15mg/kg weight according to weight, i.e.,
2.2mg/0.22kg~2.7mg/0.18 kg.The equivalent dosage to convert as people（Rat dosage is human body equivalent dose
6.3 again）For 1.587~2.381 mg/kg weight.
24 hours after the last administration, cervical dislocation put to death rat.It is moved along aorta petal to common iliac artery bifurcation stripping overall length
Arteries and veins, normal saline flushing, 4% formaldehyde are fixed, and graded ethanol dehydration, paraffin embedding cuts 4 μm of thin slices, hematoxylin eosin staining,
It is prepared into pathological section.Every animal randomly selects 6 slices, and arterial disease is observed by microscope downlink histopathologic examination,
And carry out lesion rank scores.Every animal lesion score be subject to 6 slice in the highest slice of severity.
Statistical data carries out statistical disposition using 20. 0 softwares of SPSS.The comparison among groups of arterial disease classification are using non-
Parameter rank sum test.P<0. 05 are considered as difference with statistical significance.
Arterial disease classification is scored with reference to following table：
Each group animal artery atherosclerotic lesion classification results and rank sum test result see the table below：
Compared with first group：A p<0.01.Compared with the 5th group：B p<0.01；C p<0.05.
As seen from the above table, the 6th group i.e. Miltefosine group, pathological grading mean rank order are higher than first group i.e. model group, prompt
The trend for existing and aggravating atherosclerosis is used alone in Miltefosine.
5th group of group, that is, sodium ferulate group, pathological grading mean rank order are substantially less than first group i.e. model group（p<0.01）,
Sodium ferulate is prompted, which to be used alone, has anti-atherosclerotic effect.
Second to the 4th group i.e. experimental drug group pathological grading mean rank order is substantially less than the 5th group i.e. sodium ferulate group（p<
0.05 or p<0.01）, wherein the 4th group of pole is substantially less than the 5th group（p<0.01）, illustrate that Miltefosine group is combined with sodium ferulate
During administration, instead so that sodium ferulate anti-atherosclerotic effect is improved.Prompting Miltefosine resists sodium ferulate
Atherosclerosis effect has synergistic effect.
Claims (9)
- A kind of 1. purposes of pharmaceutical composition in treatment of atherosclerosis drug is prepared, which is characterized in that the medicine group Object is closed to be made of pharmaceutically acceptable pharmaceutic adjuvant, sodium ferulate and Miltefosine；Ferulic acid in described pharmaceutical composition The weight part ratio of sodium and Miltefosine is：21~32 parts by weight of sodium ferulate, 20~28 parts by weight of Miltefosine；The medicine group Conjunction object is oral solid formulation.
- 2. purposes according to claim 1, which is characterized in that sodium ferulate and Miltefosine in described pharmaceutical composition Weight part ratio is：22 parts by weight of sodium ferulate, 27 parts by weight of Miltefosine.
- 3. purposes according to claim 1, which is characterized in that sodium ferulate and Miltefosine in described pharmaceutical composition Weight part ratio is：26 parts by weight of sodium ferulate, 25 parts by weight of Miltefosine.
- 4. purposes according to claim 1, which is characterized in that sodium ferulate and Miltefosine in described pharmaceutical composition Weight part ratio is：31 parts by weight of sodium ferulate, 22 parts by weight of Miltefosine.
- 5. purposes according to any one of claims 1 to 4, which is characterized in that the human body of described pharmaceutical composition is given daily Pharmaceutical quantities are calculated as 1.58~2.39mg/kg weight with Miltefosine.
- 6. purposes according to any one of claims 1 to 4, which is characterized in that the oral solid formulation is granule.
- 7. purposes according to claim 6, which is characterized in that the pharmaceutic adjuvant of the granule is by beta-cyclodextrin, γ-ring Dextrin, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, PVP K30 and water composition.
- 8. purposes according to claim 7, which is characterized in that beta-cyclodextrin dosage is sodium ferulate weight in the granule 0.6 times of amount, gamma-cyclodextrin dosage are 0.4 times of sodium ferulate weight, and microcrystalline cellulose dosage is the 1 of sodium ferulate weight Times, low-substituted hydroxypropyl cellulose dosage is 0.17 times of sodium ferulate weight, and PVP K30 dosage is sodium ferulate weight 0.17 times.
- 9. purposes according to claim 8, which is characterized in that the granule is prepared via a method which：The first step：Take recipe quantity sodium ferulate, Miltefosine, beta-cyclodextrin, gamma-cyclodextrin, microcrystalline cellulose, low-substituted hydroxypropyl The sieve of 80 mesh excessively is spare respectively for cellulose, PVP K30, and PVP K30 is taken to add water that the aqueous solution that mass percentage concentration is 4% is made It is spare；Second step：Recipe quantity beta-cyclodextrin, gamma-cyclodextrin mixing are taken, the water for adding in 6 times of weight of beta-cyclodextrin is ground into paste, It adds in colloid mill, adds in recipe quantity sodium ferulate and Miltefosine, grind 45 minutes, be spray-dried to obtain cyclodextrin inclusion compound Grain；Third walks：Cyclodextrin encapsulated composition granule obtained by second step is taken to cross 60 mesh sieve, adds in recipe quantity microcrystalline cellulose, low substitution hydroxyl Third cellulose mixes, add in the first step obtained by PVP K30 aqueous solution, prepare softwood, cross the granulation of 30 mesh wet sieving diameters, wet granular in 18 mesh sieve whole grain is crossed after 60 DEG C of dryings, is distributed into aluminium plastic bag to obtain the final product.
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