CN108926562A - The new application of Ciclopirox Olamine - Google Patents
The new application of Ciclopirox Olamine Download PDFInfo
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- CN108926562A CN108926562A CN201710385946.8A CN201710385946A CN108926562A CN 108926562 A CN108926562 A CN 108926562A CN 201710385946 A CN201710385946 A CN 201710385946A CN 108926562 A CN108926562 A CN 108926562A
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
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Abstract
The present invention provides the new applications of Ciclopirox Olamine.Specifically, the present invention provides Formulas I compound represented or the purposes of its solvate or its pharmaceutically acceptable salt, they be used to prepare pharmaceutical composition or preparation, described pharmaceutical composition or preparation are expected to develop into the lead compound or drug of the relevant the nervous system disease for the treatment of Blood Brain Barrier (BBB) permeability for improving and/or repairing Blood Brain Barrier (BBB) permeability.
Description
Technical field
The present invention relates to pharmaceutical technology fields, and in particular, to Ciclopirox Olamine is improving and/or repairing Blood Brain Barrier (BBB) permeability
In application.
Background technique
Blood-brain barrier be barrier between blood plasma and brain cell that brain capillary wall and Deiter's cells are formed and by
The barrier between blood plasma and cerebrospinal fluid that choroid plexus is formed, these barriers allow hydrone, gas molecule, fat-soluble small molecule
Pass through, while the relevant sugar of some nervous functions of active transport and amino acid；It is important that it prevents Cucumber from (having mostly
It is harmful) brain tissue entered by blood, protect brain tissue few by even not by the infringement of harmful substance in blood, to keep inner ring
Border it is basicly stable, to maintain nervous system normal physiological condition have important biological significance.
The destruction of blood-brain barrier is closely related with the occurrence and development of numerous the nervous system diseases, such as cranial vascular disease, cranium
Interior infection, Neurogenic inflammatory, brain edema, hepatic encephalopathy, epilepsy and brain tumor etc..In cranial vascular disease；Blood-brain barrier participates in
Due to bleeding that aberrant angiogenesis has been sent out in familial cerebral cavernous angioma；The ataxia caused by epilepsy, Alexander ' s
Disease, leukoencephalopathy and partial epilepsy tolerance drug therapy are related to the function of blood-brain barrier；Cerebral ischemia, it is scorching
Disease reaction, brain tumor, the brain edema that altitude sickness is induced are influenced by blood-brain barrier function；In intracranial infection, blood brain screen
Barrier can prevent common pathogen (such as bacterial virus), and immunodeficiency virus and malaria enter nervous system；Blood brain screen simultaneously
Barrier also will affect neuroinflamation, the process and prognosis of the nervous system diseases such as brain tumor and hepatic encephalopathy.
Therefore the drug that can improve and/or repair Blood Brain Barrier (BBB) permeability is found in improvement, prevention and treatment brain diseases
Such as it plays a significant role in the nervous system disease.
Summary of the invention
The purpose of the present invention is to provide small molecule compound Ciclopirox Olamines to improve and/or repair in Blood Brain Barrier (BBB) permeability
Application；Or active constituent or lead compound as Blood Brain Barrier (BBB) permeability treating correlative diseases drug, related disease include
Cranial vascular disease, intracranial infection, Neurogenic inflammatory, brain edema, hepatic encephalopathy, epilepsy and brain tumor etc..
In the first aspect of the present invention, provide a kind of Formulas I compound represented or its solvate or its pharmaceutically
The purposes of acceptable salt is used to prepare pharmaceutical composition or preparation, and described pharmaceutical composition or preparation are for improving and/or repairing
Multiple Blood Brain Barrier (BBB) permeability；
In another preferred example, the Blood Brain Barrier (BBB) permeability is non-vascular disruptiveness Blood Brain Barrier (BBB) permeability.
In another preferred example, the Blood Brain Barrier (BBB) permeability is selected from：Caused by ischemic Blood Brain Barrier (BBB) permeability, vascular sclerosis
Blood Brain Barrier (BBB) permeability caused by Blood Brain Barrier (BBB) permeability, Reperfu- sion.
In another preferred example, the Blood Brain Barrier (BBB) permeability is selected from：Cranial vascular disease, intracranial infection, Neurogenic inflammatory, brain
The nervous system disease relevant to blood-brain barrier such as oedema, hepatic encephalopathy, epilepsy and brain tumor.
In another preferred example, 0.001-99wt% is contained in described pharmaceutical composition, preferably 0.1-90wt%, more preferably
The compound of formula I of ground 1-80wt% or its solvate or its pharmaceutically acceptable salt, are based on the total weight of the composition.
In the second aspect of the present invention, a kind of pharmaceutical composition improved and/or repair Blood Brain Barrier (BBB) permeability is provided, is contained
Have：
(a) compound of formula I or its pharmaceutically acceptable salt；And
(b) pharmaceutically acceptable carrier.
In another preferred example, the pharmaceutical composition further includes：
(c) antioxidant, anti-inflammatory agent, neuroprotective agent, or combinations thereof.
In another preferred example, the antioxidant is selected from the group：Epiphysin, vitamin E, vitamin C, Idebenone,
Root of red-rooted salvia phenolic acid, or combinations thereof.
In another preferred example, the anti-inflammatory agent is selected from the group：Aspirin, Indomethacin, brufen, Rosiglitazone,
Or combinations thereof.
In another preferred example, the neuroprotective agent is selected from the group：Nimodipine, curcumin, Memantine, born of the same parents' phosphorus gallbladder
Alkali, or combinations thereof.
In another preferred example, the dosage form of described pharmaceutical composition be injection, tablet, capsule, pill, suspending agent or
Emulsion.
In another preferred example, the dosage form of described pharmaceutical composition is peroral dosage form, transdermal, vein or intramuscular injection
Dosage form.
It should be understood that above-mentioned each technical characteristic of the invention and having in below (eg embodiment) within the scope of the present invention
It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, exist
This no longer tires out one by one states.
Detailed description of the invention
Protective effect of Figure 1A Ciclopirox Olamine to blood-brain barrier after ischemia-reperfusion, intracerebral Evans indigo plant ooze out result signal
Figure.
Protective effect of Figure 1B Ciclopirox Olamine to blood-brain barrier after ischemia-reperfusion, Evans indigo plant exudation statistics in brain tissue
Figure；#p<0.05 compared with sham-operation group,*p<0.05 compared with solvent control group, n=4~7.
Specific embodiment
The present inventor has unexpectedly discovered Ciclopirox Olamine by depth studying extensively for the first time (structure is shown in formula I)
It can significantly improve blood brain barrier of rats damage.It is significant that experiment shows that the compound of formula I has blood brain barrier of rats damage
Improvement result, formula Compound I can be used for improving and/or repairing Blood Brain Barrier (BBB) permeability, for treatment, improve and/
Or the relevant the nervous system disease of prevention Blood Brain Barrier (BBB) permeability.On this basis, the present invention is completed.
Active constituent
As used herein, term " the compounds of this invention " refers to formula (I) compound represented.The term further includes and formula (I)
Compound or its various pharmaceutically acceptable salt.It should be understood that the term further includes the mixture of said components.
As used herein, term " pharmaceutically acceptable salt " be refer to retain free alkali biological effectiveness and without it
Its side effect, salt is formed by with inorganic acid or organic acid.Inorganic acid salt includes but is not limited to hydrochloride, hydrobromate, sulphur
Hydrochlorate, nitrate, phosphate etc.；Acylate includes but is not limited to formates, acetate, 2,2- dichloroacetate, trifluoro second
Hydrochlorate, propionate, caproate, caprylate, caprate, undecylenate, glycollate, gluconate, lactate, decanedioic acid
Salt, adipate, glutarate, malonate, oxalates, maleate, succinate, fumarate, tartrate, lemon
Hydrochlorate, palmitate, stearate, oleate, cinnamate, laruate, malate, glutamate, pyroglutamate,
Aspartate, benzoate, mesylate, benzene sulfonate, tosilate, alginate, ascorbate, salicylic acid
Salt, 4-ASA salt, napadisilate etc..
These salt can be prepared by known salifying method by the compound of Formulas I.
Compound of formula I of the invention can be used method well known to those skilled in the art in the prior art and be prepared, right
The response parameter of each step is not particularly limited.In addition, typical compound of the invention can also be obtained by commercially available mode.
Ciclopirox Olamine causes intracellular object as broad-spectrum antifungal medicine, the main integrality by changing fungal cell membrane
Matter outflow, and the intake of blocking protein precursor substance cause fungal cell dead, have to dermatophyte, saccharomycete, mould etc.
There is stronger antibacterial and bactericidal effect, permeability is strong.However there has been no document report Ciclopirox Olamines to improve blood-brain barrier at present
Dependent interaction in damage.
Blood Brain Barrier (BBB) permeability
Under pathological conditions, astroglia and endothelial cell are influenced by certain factors, its structure is caused to become
Change, permeability increases, and in turn results in blood-brain barrier and is destroyed.In many central nervous system diseases, due to cellular damage or
Activation leads to the release or activation of medium, so as to cause barrier dysfunction.These vaso-active substances are probably derived from blood,
Axoneure or endothelial cell itself.The bradykinin of haemocyte release and the activation of complement system will increase the logical of BBB
The T cell of permeability, while blood platelet, basophilic granulocyte, macrophage and activation can discharge the substance of destruction BBB such as：Group
Amine, serotonin, leukotriene, prostaglandin, tumor necrosis factor etc..Nerve cell release bradykinin that is impaired or being disturbed,
Histamine, interleukin and free radical etc. destroy BBB, and in the brain cell external solution of intracerebral lesion arachidonic content increases, and
With its metabolite prostaglandin, leukotriene increases cerebrovascular permeability together.
Purposes
Since the compounds of this invention has the function of significantly improving blood brain barrier of rats damage, the compounds of this invention
And its pharmaceutically acceptable inorganic or organic salt, and containing the compounds of this invention be main active pharmaceutical composition
It can be used for treating, prevent and alleviate the nervous system disease mediated by Blood Brain Barrier (BBB) permeability.
In the present invention, the example of the nervous system disease mediated by Blood Brain Barrier (BBB) permeability includes (but being not limited to) brain blood
Pipe disease, intracranial infection, Neurogenic inflammatory, brain edema, hepatic encephalopathy, epilepsy and brain tumor etc..
Pharmaceutical composition and method of administration
Pharmaceutical composition of the invention includes the compounds of this invention within the scope of safe and effective amount or its is pharmaceutically acceptable
Salt and pharmaceutically acceptable excipient or carrier.Wherein " safe and effective amount " refers to：The amount of compound is enough obviously
Improve the state of an illness, and is unlikely to generate serious side effect.In general, pharmaceutical composition contains 1-2000mg the compounds of this invention/agent,
More preferably, containing 5-100mg the compounds of this invention/agent.Preferably, described is " one " for a capsule or tablet.
" pharmaceutically acceptable carrier " refers to：One or more biocompatible solids or liquid filler or jello
Matter, they are suitable for people's use and it is necessary to have enough purity and sufficiently low toxicity." compatibility " referred to herein as combines
In object each component energy and the compound of the present invention and they between mutually admix, and significantly reduce the drug effect of compound.Medicine
Acceptable carrier part example has cellulose and its derivates (such as sodium carboxymethylcellulose, ethyl cellulose sodium, fibre on
Tie up plain acetic acid esters etc.), gelatin, talcum, solid lubricant (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soya-bean oil, sesame
Sesame oil, peanut oil, olive oil etc.), polyalcohol (such as propylene glycol, glycerol, mannitol, sorbierite), emulsifier (such as )、
Wetting agent (such as lauryl sodium sulfate), colorant, flavoring agent, stabilizer, antioxidant, preservative, apirogen water.
The method of application of the compounds of this invention or pharmaceutical composition is not particularly limited, and representative method of application includes
(but being not limited to)：Oral, parenteral (intravenous, intramuscular or subcutaneous).
Solid dosage forms for oral administration includes capsule, tablet, pill, powder and granule.In these solid formulations
In type, reactive compound is mixed at least one conventional inert excipients (or carrier), such as sodium citrate or Dicalcium Phosphate, or with
Following compositions mixing：(a) filler or expanding material, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid；(b) it bonds
Agent, for example, hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and Arabic gum；(c) moisturizer, example
Such as, glycerol；(d) disintegrating agent, for example, agar, calcium carbonate, potato starch or tapioca, alginic acid, certain composition silicates,
And sodium carbonate；(e) retarding solvent, such as paraffin；(f) absorbsion accelerator, for example, quaternary ammonium compound；(g) wetting agent, such as spermaceti
Pure and mild glycerin monostearate；(h) adsorbent, for example, kaolin；(i) lubricant, for example, talcum, calcium stearate, tristearin
Or mixtures thereof sour magnesium, solid polyethylene glycol, lauryl sodium sulfate,.In capsule, tablet and pill, dosage form also may include
Buffer.
Coating and shell material preparation can be used in solid dosage forms such as tablet, sugar-pill, capsule, pill and granule, such as casing and
Other materials well known in the art.They may include opacifying agent, also, reactive compound or compound in this composition
Release can discharge in certain a part in the digestive tract in a delayed fashion.The example of adoptable embedding component is polymeric material
And wax material.When necessary, reactive compound can also be with one of above-mentioned excipient or a variety of formation microencapsulation forms.
Liquid formulation for oral administration includes pharmaceutically acceptable lotion, solution, suspension, syrup or tincture.
In addition to active compounds, liquid dosage form may include the inert diluent routinely used in this field, such as water or other solvents, increase
Solvent and emulsifier, example know, ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-BDO, dimethyl formyl
The mixture of amine and oil, especially cottonseed oil, peanut oil, maize germ, olive oil, castor oil and sesame oil or these substances
Deng.
Other than these inert diluents, composition also may include auxiliary agent, such as wetting agent, emulsifier and suspending agent, sweet taste
Agent, corrigent and fragrance.
In addition to active compounds, suspension may include suspending agent, for example, ethoxylation isooctadecane alcohol, polyoxyethylene
Sorbierite and Isosorbide Dinitrate, microcrystalline cellulose, aluminium methoxide and agar or the mixture of these substances etc..
Composition for parenteral injection may include physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid,
Suspension or lotion, and the aseptic powdery for re-dissolving into sterile Injectable solution or dispersion liquid.It is suitable aqueous and
Nonaqueous carrier, diluent, solvent or excipient include water, ethyl alcohol, polyalcohol and its suitable mixture.
The compounds of this invention can be administered alone, or be administered in combination with other pharmaceutically acceptable compounds.
It is the mammal that the compounds of this invention of safe and effective amount is applicable to treatment when using pharmaceutical composition
(such as people), wherein dosage is the effective dosage pharmaceutically thought when application, for the people of 60kg weight, day is to medicament
Amount is usually 1~2000mg, preferably 5~100mg.Certainly, specific dosage be also contemplated that administration route, patient health situation etc. because
Element, within the scope of these are all skilled practitioners technical ability.
Main advantages of the present invention include：
(1) present invention firstly discovers that Ciclopirox Olamine has the function of protecting blood-brain barrier from damage, and clinically mostly
The occurrence and development of number the nervous system disease are related to blood-brain barrier disruption, therefore Ciclopirox Olamine is likely to become treatment nerve
The first-line drug of systemic disease.
(2) the invention belongs to old medicines newly to use, Ciclopirox Olamine be marketed drug, pharmacokinetics and toxicologic study compared with
Be it is clear, in the case where current new drug development is very difficult, the exploitation of use of approved drugs for nonapproved uses can greatly save the development time and
Cost reduces risk and improves the success rate of new drug development.
(3) Ciclopirox Olamine is listed as antifungal drug, and the present invention can treat nervous system disease to increase Ciclopirox Olamine
The new application of disease provides foundation.
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip
Part, such as Sambrook et al., molecular cloning：Laboratory manual (New York: Cold Spring Harbor
Laboratory Press, 1989) condition described in, or according to the normal condition proposed by manufacturer.Unless otherwise stated, no
Then percentage and number are calculated by weight.Raw materials used or instrument in the embodiment of the present invention, if not illustrate, it is commercially available can
?.
Material
Ciclopirox Olamine is purchased from Sigma-Aldrich company
1 ring of embodiment improves the activity of blood brain barrier of rats damage than ketoamine
1.1 test method
Ring is detected than ketoamine to the improvement result of Blood Brain Barrier (BBB) permeability, specific method and experiment step using Evans blue party method
It is rapid as follows：
The operation modeling of Rats With Unilateral arteria cerebri media embolism is carried out using the method for Longa et al. report1, cause rat serum
Brain barrier injury.Neck median incision, chorista, exposure left side external carotid artery (ECA) and internal carotid (ICA) crotch,
Connection thin vessels between the subbranch blood vessel and ECA and ICA of coagulation ECA lift arteria carotis communis with the nylon wire of 3-0
(CCA), ICA is closed with artery clamp folder, ligatures ECA distal end, angular cut is cut on ECA, head end is scalded to No. 2838 embolism lines of circle
(offer of Beijing Sha Dong biotech firm) insertion, unclamps the artery clamp on ICA, and embolism line enters ICA by ECA, is advanced into greatly along ICA
Artery (MCA) in brain has obvious resistance sense to stop and (count about 19~20mm of insertion from ECA and ICA crotch) at this time.Ligation
ECA unclamps the nylon wire of lifting CCA, after operation, sutures skin of neck, and slowly extracting embolism line after ischemic 2h out is again
Perfusion；It is steam again after awake, ad lib.Sham-operation group, the same ischemia group of operating procedure, only rests on ICA without entering for embolism line
Cranium does not block MCA.
In brain blood flow Reperfu- sion, tail vein gives compound Ciclopirox Olamine 3mg/kg simultaneously, and model group is given the same dose of
Physiological saline.Continue to raise 72 hours after the operation of arteria cerebri media embolism, intravenous injection Evans indigo plant (2% Evans indigo plant solution,
4ml/kg), after blood circulation in 2 hours, left and right brain is collected respectively until not having blood with saline infusions, weighs, is added
50% trichloroacetic acid of 1ml is homogenized (precelly homogenizer), is centrifuged 10000g x 20 minutes, 200 μ L of supernatant adds
Enter in clear microplate (96 hole), detection absorbs light, and wavelength 620nm is corresponding dense according to standard curve 0.2-10 μ g/ml conversion
Degree2。
1.2 test result
As shown in FIG. 1A and 1B, the results showed that compound Ciclopirox Olamine significantly improves the work of blood brain barrier of rats damage
With.Therefore, the present invention relates to compounds to be expected to exploitation into treatment, improvement and/or prevention Blood Brain Barrier (BBB) permeability related neurological
The drug and/or pharmaceutical composition of disease.
As the result is shown (Figure 1A), compared with sham-operation group, give in the model group brain tissue of solvent control has Evans indigo plant
A large amount of Evans indigo plant exudation, indicates that blood-brain barrier is seriously damaged, and it is bright to give Evans indigo plant in Ciclopirox Olamine tissues following MCAO in rats
It is aobvious to reduce, show that compound can reduce the exudation of Evans indigo plant, protects blood-brain barrier from damage；Statistical result (Figure 1B)
In, compared with sham-operation group, in model group the exudation ratio (damage side/opposite side) of Evans indigo plant risen to 4.48 from 0.64 (#
p<0.05 with sham-operation group ratio), give ratio after Ciclopirox Olamine have decreased to 1.79 (*p<0.05 compared with solvent control group),
Show that compound Ciclopirox Olamine has the function of inhibiting Evans indigo plant exudation protection blood-brain barrier.
All references mentioned in the present invention is incorporated herein by reference, independent just as each document
It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can
To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims
It encloses.
Bibliography：
1 Longa E Z,Weinstein P R,Carlson S,et al.Reversible middle cerebral
artery occlusion without craniectomy in rats.stroke,1989, 20(1):84-91.
2 Belayev L,Busto R,Zhao W,et al.Quantitative evaluation of blood-
brain barrier permeability following middle cerebral artery occlusion in rats
[J].Brain research,1996,739(1):88-96。
Claims (10)
1. the purposes of a kind of Formulas I compound represented or its solvate or its pharmaceutically acceptable salt, which is characterized in that
It is used to prepare pharmaceutical composition or preparation, described pharmaceutical composition or preparation are for improving and/or repairing Blood Brain Barrier (BBB) permeability；
2. purposes as described in claim 1, which is characterized in that the Blood Brain Barrier (BBB) permeability is selected from：Ischemic blood-brain barrier damage
Blood Brain Barrier (BBB) permeability caused by Blood Brain Barrier (BBB) permeability, Reperfu- sion caused by wound, vascular sclerosis.
3. purposes as described in claim 1, which is characterized in that contain in the pharmaceutical composition described pharmaceutical composition
0.001-99wt%, preferably 0.1-90wt%, the more preferably compound of formula I of 1-80wt% or its solvate or its pharmacy
Upper acceptable salt, is based on the total weight of the composition.
4. the pharmaceutical composition of a kind of improvement and/or reparation Blood Brain Barrier (BBB) permeability, which is characterized in that contain：
(a) compound of formula I or its pharmaceutically acceptable salt；And
(b) pharmaceutically acceptable carrier.
5. pharmaceutical composition as claimed in claim 4, which is characterized in that further include：
(c) antioxidant, anti-inflammatory agent, neuroprotective agent, or combinations thereof.
6. pharmaceutical composition as claimed in claim 5, which is characterized in that the antioxidant is selected from the group：Epiphysin, dimension life
Plain E, vitamin C, Idebenone, root of red-rooted salvia phenolic acid, or combinations thereof.
7. pharmaceutical composition as claimed in claim 5, which is characterized in that the anti-inflammatory agent is selected from the group：Aspirin, indoles
Mei Xin, brufen, Rosiglitazone, or combinations thereof.
8. pharmaceutical composition as claimed in claim 5, which is characterized in that the neuroprotective agent is selected from the group：Nimodipine,
Curcumin, Memantine, citicoline, or combinations thereof.
9. pharmaceutical composition as claimed in claim 4, which is characterized in that the dosage form of described pharmaceutical composition is injection, piece
Agent, capsule, pill, suspending agent or emulsion.
10. pharmaceutical composition as claimed in claim 4, which is characterized in that the dosage form of described pharmaceutical composition be peroral dosage form,
Transdermal, vein or intramuscular injection dosage form.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP4193989A1 (en) * | 2021-12-09 | 2023-06-14 | Atlas Molecular Pharma, S.L. | A formulation for an effective oral administration of ciclopirox with no adversal gasterointestinal toxicity |
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| CN101233151A (en) * | 2005-07-27 | 2008-07-30 | 纳斯泰克制药公司 | Tight junction modulating peptide components for enhancing mucosal delivery of therapeutic agents |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP4193989A1 (en) * | 2021-12-09 | 2023-06-14 | Atlas Molecular Pharma, S.L. | A formulation for an effective oral administration of ciclopirox with no adversal gasterointestinal toxicity |
| WO2023105031A1 (en) * | 2021-12-09 | 2023-06-15 | Atlas Molecular Pharma, S.L. | A formulation for an effective oral administration of ciclopirox with no adversal gasterointestinal toxicity |
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Application publication date: 20181204 |