Efficient lipid delivery to human tear film using a salt-sensitive emulsion system.
Abstract
A salt-free emulsion for the treatment of dry eye and other eye conditions is described, which contains castor oil and does not contain olive oil, which prolongs the TBUT provides superior comfort.

Term
6.2 yearsleft in the term
Expires 7 December 2032.
- Priority
- Filed
- Granted
- Today
- Expires
1 claim: 1 independent, 0 dependent
- 1REIVINDICACIONES IMPI INSTITUTO MKXICANO OS LA SROflf-DAO ÍNOUSTWAL Habiéndose descrito la invención como antecede, se reclama como propiedad lo contenido en las siguientes reivindicaciones:1. Una composición farmacéutica oftálmica baja en sal, caracterizada porque comprende una emulsión submicrométrica, un lubricante polimérico, y un polímero modulador de viscosidad sensible a la sal, en donde la emulsión sub-micrométrica comprende un tensioactivo y un lípido terapéutico que consiste esencialmente de aceite de ricino. 2. La composición farmacéutica oftálmica baja en sal de conformidad con la reivindicación 1, caracterizada porque el lípido terapéutico es aceite de ricino presente en una concentración de 0.25% (p/p). 3. La composición farmacéutica oftálmica baja en sal de conformidad con la reivindicación 1, caracterizada porque el tensioactivo es un éster de sorbitán, en donde el éster de sorbitán es polisorbato 80 presente en una concentración de 0.5% (p/p). 4. La composición farmacéutica oftálmica baja en sal de conformidad con la reivindicación 1, caracterizada porque el polímero modulador de viscosidad sensible a la sal es un polímero cruzado de acrilato/acrilato C10-C30 que tiene en donde el polímero modulador de viscosidad sensible a la sal está presente en una concentración de 0.1% (p/p)· 5. La composición farmacéutica oftálmica baja en sal de conformidad con la reivindicación 1, caracterizada porque el lubricante polimérico es sodio de carboximetilcelulosa presente en una concentración de 0.5% (p/p)· 6. La composición farmacéutica oftálmica baja en sal de conformidad con la reivindicación 1, caracterizada porque además comprende un soluto compatible. 7. La composición farmacéutica oftálmica baja en sal de conformidad con la reivindicación 6, caracterizada porque el soluto compatible es eritritol y levocarnitina. 8. La composición farmacéutica oftálmica baja en sal de conformidad con la reivindicación 7, caracterizada porque comprende eritritol en una concentración de 0.25% (p/p) y levocarnitina en una concentración de 0.25% (p/p). 9. La composición farmacéutica oftálmica baja en sal de conformidad con la reivindicación 1, caracterizada porque además comprende un agente de tonicidad, en donde el agente de tonicidad es glicerina presente en una concentración de 1.0% (p/p). 10. La composición farmacéutica oftálmica baja en sal de conformidad con la reivindicación 1, caracterizada IMPI INSTITUTO MEXICANO Oí LA ΡΛΟΓΙΕΠΑΟ INCUÍTRIAL porque además comprende un conservador. 11. La composición farmacéutica oftálmica baja en sal de conformidad con la reivindicación 10, caracterizada porque el conservador es un complejo de oxicloro estabilizado presente en una concentración de 0.01% (p/p). 12. La composición farmacéutica oftálmica baja en sal de conformidad con la reivindicación 1, caracterizada porque además comprende un amortiguador. 13. La composición farmacéutica oftálmica baja en sal de conformidad con la reivindicación 12, caracterizada porque el amortiguador es ácido bórico presente en una concentración de 0.6% (p/p). 14. La composición farmacéutica oftálmica baja en sal de conformidad con la reivindicación 1, caracterizada porque además comprende un agente de ajuste de pH. 15. La composición farmacéutica oftálmica baja en sal de conformidad con la reivindicación 14, caracterizada porque el agente de ajuste de pH es NaOH. 16. La composición farmacéutica oftálmica baja en sal de conformidad con la reivindicación 14, caracterizada porque tiene pH de 7.3. 17. Una composición farmacéutica oftálmica baja en sal, caracterizada porque comprende: un lípido terapéutico que consiste esencialmente de aceite de ricino en una concentración de 0.25% (p/p);INSTITUTO MEXICANO ίχ, ·~'7: -.,' ς. ΟΕΙΑΛΟΟΚΙΛ» polisorbato 80 en una concentración de ^/ u 5*l^(p/pT;polímero cruzado de acrilato/acri-late^r· -ery* concentración de 0.1% (p/p), en donde el polímero cruzado de acrilato/acrilato C10-C30 tiene una viscosidad de emulsión estándar entre 1,700 y 4,5000 cPs;sodio de carboximetilcelulosa en una concentración de 0.5% (p/p);glicerina en una concentración de 1.0% (p/p);un conservador de complejo de oxicloro estabilizado en una concentración de 0.01% (p/p);ácido bórico en una concentración de 0.6% (p/p);eritritol en una concentración de 0.25% (p/p);levocarnitina en una concentración de 0.25% (p/p) NaOH;y agua. sal de método 18. Una conformidad para tratar composición farmacéutica oftálmica baja con la reivindicación 1 para usarse en síndrome de ojo seco. en un INSTITUTO MEXICANO De LA l-ROHEDAD INDUSTRIAL
306 paragraphs in 32 sections, as filed
(57) Summary
A salt-free emulsion is described for the treatment of dry eye and other eye conditions, which contains castor oil and does not contain olive oil, which prolongs TBUT provides superior comfort.
(57) Abstract
A salt-free emulsion for the treatment of dry eye and other ocular conditions is disclosed which contains castor olí and does not contain olive olí which prolongs TBUT and provides superior comfort.
IMPTC
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PATENT TITLE No. 355216
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Headlines):
ALLERGAN, INC.
Home:
2525 Dupont Drive, Irvine, California, 92612, USA
D nomination:
Classification:
Inventor (s):
EFFICIENT ADMINISTRATION OF LIPIDS TO THE HUMAN LAGRIMAL FILM THROUGH THE USE OF A SALT SENSITIVE EMULSION SYSTEM.
A61K31 / Q47; A61K9 / | 0 | A ^ 1I ^ M07 ^ A61K31 / 341; A61K31 / 717; A61K47 / 32 A61K31 /O47;.A61 K9 / 0048; Α6> Κ9 / 1 $ 7; A61K31 / 341; A61K31 / 717; A6ÍK47 / 3¿ '·', JOSEP ^ t'VEHIGE; PETE
CIP: CPC:
Number:
MX / a / 2014/006804
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tional:
♦
Number:
61/568,089
61/625,401
Country: ”crsU§ ^
WO
Validity: Veinié. years
Expiration Date
F cha of EjiR4 <ftc¡óní '<0 4Íé' | bri |. ^ 018
The reference patent ^ grants based on the articles
TW .- / ”
In accordance with artM * | to (Je the Law Data Proprietary from the date of submission of TMJ, ® the international application and will be under Industrial Property.
je 4ñó. »1frorrogables, told ks rights.
Who subscribes to this title fun <amacttg<sub>TO</sub>in what you enjoyed & 5 · 4ίουΐφ6- “ίΤ89Ριάββ» · ΙΙΙ and Jrt »s2 of the Industrial Property Law (Official Gazette of the Federation <Dt> 7t) 27 / Ó8 / 199 <rMprmaila on # 2 * 871994, 36 / 10 * (^ 12/26/1997<sup>1</sup>. 05/17/1999, 01/26/2004, 06/16/2005, 01/25/2006, 06/05/2009, 06/01/2010,, ie¡te / 2¡ »<0,« 8 / 06/204 $ 27 / Λ / 2012 Xoto / 2O12k ajücu ^<sup>0</sup>, 3VraeÉjénVinci «S a), 4 'and 12' sections I and III of the Regulations of the Mexican Institute dtHaettWSad Irtdwtrial '(0» dg 14Matl9993 «lormado ^ gl 01®7 ^ 2ácí, <l5 / 07/2004. 28/07 / 2004 and 7/09/2007); Articles 1, 3, 4, 5, fraction V subsection a) / lj · II and 30 déPHWáfeWurgánjpo itirf & MeXléáno of Industrial Property (DOF
12/27/1999, amended on 10/10/2002, 29 / 077® '' ^ MPIO ^); 3 '”Atftrdo that delegates powers to the Directors
Deputy Generals. Coordinator. Directors, Divisional Deputy Directors, Coordinated res
Departmental and other subordinates of the Instituto Mexi laW ^ h ^ nd r 12/15/1999, amended on 04/02/2000, 07/29/2004,
08/04/2004 and 09/13/2007).
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zn ..
This document is signed with an advanced electronic signature (FIEL), based on articles 7 BIS 2 of the Industrial Property Law; 3rd of its Regulations, and 1 section III, 2 section V, 26 BIS and 26 TER of the Agreement establishing the guidelines for the use of the Electronic Payment and Services Portal (PASE) of the Mexican Institute of Industrial Property, in the procedures indicated.
THE DIVISIONAL PATENT DIRECTOR
NAHANNY CANAL REYES
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NAHANNY MARISOL CANAL REYES | 00001000000403252793 | Administration Service
Tax | 1695 || MX / 2018/29568 | MX / a / 2014/006804 | PCT patent title | 1027 | RGZ | Page (s) | Q5tHKPkwOuAP2k + XoxrOzdk3Q / k =
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Arenal No. 550 Riso 1, Santa María Tepepan Town, Xochimilco. 16020, Mexico City (55) 53340700 www.gob.mx/impi
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I AldRJL
ΙΝ5ΤγΠΓπ> MEXICANO DI LA INDUSTRIAL PROPERTY
EFFICIENT ADMINISTRATION OF LIPIDS TO THE FILM
HUMAN LAGRIMAL THROUGH THE USE OF A SALT SENSITIVE EMULSION SYSTEM
FIELD OF THE INVENTION
The present invention relates to artificial tears suitable for treating dry eye syndrome and other eye disorders in humans or other mammals.
BACKGROUND OF THE INVENTION
Typical symptoms of keratoconjunctivitis or dry eye include a feeling of dryness, burning and a lumpy, sandy eye feeling that can get worse throughout the day. Symptoms such as itching, roughness, stinging or tiredness of the eyes can also be described. Other symptoms include pain, redness, tightness and pressure behind the eye. Damage to the ocular surface that results from dry eye increases discomfort and sensitivity to strong lights. Generally, both eyes are usually affected.
Because the blinking covers the eyes with tears, the symptoms get worse with activities in which the frequency of blinking is reduced due to prolonged use of the eyes. These activities include prolonged reading, computer use, vehicle driving or the use of television.
Symptoms increase in windy areas
Ref.:249310
IMPI
INSTITUTO MEX1CAHO os la wrwrea * or <MOUST1M »jj,
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dusty or smoke-filled, in ambiAr ^ ati <sub>Pamaar</sub>.....
heights even on airplanes, on low humidity days and in areas where air conditioning, fan, or heating is used. Symptoms are less severe on days of cool, rainy or foggy weather, and in humid places. Most people who have dry eyes experience mild irritation without long-term effects. However, if the disorder is not treated or becomes severe, it can cause complications that can cause eye damage, resulting in impaired vision or possibly vision loss.
Having dry eyes for a prolonged period of time can lead to tiny abrasions on the ocular surface. In advanced cases, the epithelium undergoes pathological changes, namely squamous metaplasia and loss of goblet cells due, sometimes, to the activation of T cells acting against the cells. Some severe cases result in an increase in corneal surface thickness, corneal erosion, dotted keratitis, epithelial defects, corneal ulceration, corneal neovascularization, corneal scarring, corneal thinning and even perforation. of the cornea An abnormality of any of the three layers of tears that produces an unstable tear film can result in symptoms of dry keratitis.
Dry keratoconjunctivitis
IMPI
MEXICAN INSTITUTE OF PROPERTY, JNDUSTE1AL is usually due
<img file="MX355216B_D0012.tif" />
to inadequate tear production.
The aqueous layer§á dé '· * tears is affected, resulting in a deficiency of watery tears or tear hyposcretion. The tear gland does not produce enough tears to keep the entire conjunctiva and cornea covered by a full layer. This usually occurs in people who are otherwise healthy. Advanced age is associated with a decrease in tear production. This is the most common type found in postmenopausal women.
Causes include congenital idiopathic alacrimia, xerophthalmia, tear gland ablation and sensory enervation.
In rare cases it can be a symptom of collagen vascular diseases, including rheumatoid arthritis, Wegener's granulomatosis and systemic lupus erythematosus. Sjógren's syndrome and autoimmune diseases associated with aqueous conditions. Some drugs, sedatives, diuretics.
Associated are also the deficiency of tears such as isotretinoin, tricyclic antidepressants, antihypertensives, oral contraceptives, antihistamines, nasal decongestants, beta blockers, phenothiazines, atropine and opioids for pain such as morphine can cause or worsen this condition. Infiltration in
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tear glands by sarcoidosis or
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Post-radiotherapy of the lacrimal glands can also cause this condition.
Dry keratoconjunctivitis can also be caused by an abnormal composition of tears that results in rapid evaporation or premature destruction of tears. When it is caused by rapid evaporation, it is called evaporative dry eye. In this condition, although the tear gland produces a sufficient amount of tears, the rate of evaporation of the tear is very high. There is a loss of water by the tears that results in the tears being very salty or hypertonic. As a result, the entire conjunctiva and cornea cannot be covered with a full tear layer during certain activities or in certain environments.
Aging is one of the most common causes of dry eye. This is due to the fact that tear production decreases with age. It can be caused by thermal or chemical burns or by adenovirus. Diabetics are also at a higher risk of having a dry eye.
An eye injury or other problem with the eyes or eyelids, such as prominence of the eyeball or droopy eyelid, can cause dry keratoconjunctivitis. The
ΙΜΡΙ
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'• i
MEXICAN INSTITUTE OF PROPERTY, / NDUSTR1AL
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Eyelid disorders can prevent the complex flickering movement necessary to spread tears. "
About half of the people who wear contact lenses have dry eyes.
This is because soft contact lenses, which float on the tear film that lines the cornea, absorb tears from the eyes. Dry eye also occurs or worsens after refractive surgery, in which the corneal nerves are cut when a flap is created in the cornea, because the corneal nerves stimulate the secretion of tears. Dry eyes caused by these procedures usually disappear after several months.
Abnormalities of the lipid layer of tears caused by blepharitis and rosacea, and abnormalities of the mucin layer of tears caused by a deficiency of vitamin A, trachoma, mucocutaneous disorders of diphtheria keratoconjunctivitis and certain topical medications can cause dry eye or keratoconjunctivitis dry
It is usually possible to diagnose dry eye from symptoms only. Both the quantity and quality of tears can be determined by tests. A slit lamp test can be performed to diagnose dry eyes and document any damage to the eye. A Schirmer test can measure how severe the humidity is to determine what
They can be taken differently
MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY
<img file="MX355216B_D0017.tif" />
This test is useful for the condition.
Approaches to it such as: avoid exacerbating factors, stimulate and complement tears, increase tear retention, clean the eyelid and treat eye inflammation. For mild and moderate cases, the most important part of the treatment is complementary lubrication.
The application of artificial tears every few hours can provide temporary relief.
Lubricating tear ointments can be used during the day, but they are generally used at bedtime due to poor vision resulting from their application.
They contain white petrolatum, mineral oils and similar lubricants.
They serve as a lubricant and emollient.
Depending on the severity of the condition, the ointments apply either hourly or just before bedtime. Ointments should not be used with contact lenses. Inflammation that occurs in response to the hypertonicity of the tear film can be suppressed with mild topical spheroids or with topical immunosuppressants such as cyclosporine.
SUMMARY OF THE INVENTION
The present invention comprises an emulsion of artificial tears with the following formulation:
<td colspan="3">Table I</td><td>IMPI INSTITUTO MEXICANO & - <-'íj '·'? OF THE PROPERTY < INDUSTRIAL</td>
<td>. ·!] POLISORBATE 80 Grade: NF Ph Esw</td><td> 0,5</td><td>% ρφ</td><td>Active principle</td>
<td>[2] CARBOXIMETILCELULOSADE</td><td> 0,5</td><td>% PP</td><td>Active principle</td>
<td>SODIUM (LOW VISCOSITY 7LFPH)</td><td></td><td></td><td></td>
<td>Grade: PfcEurUSP</td><td></td><td></td><td></td>
<td>3f''GQCHffi¡A ........................................... ...........</td><td> .......1.0......................</td><td>................... W</td><td>Active principle</td>
<td>Grade: PhEmVS?</td><td></td><td></td><td></td>
<td>(4] PURITA</td><td> 0,01</td><td>% pp</td><td>Preservative</td>
<td>Grade:</td><td></td><td></td><td></td>
<td></td><td></td><td></td><td></td>
<td>BORIC ACID</td><td> 0,6</td><td>% ρφ</td><td>Shock absorber</td>
<td>Grade: NFPteEar</td><td></td><td></td><td></td>
<td>[5] PEMULEN TK-2</td><td> 0,1</td><td>% pp</td><td>Stabilizer</td>
<td>Grade: NF</td><td></td><td></td><td></td>
<td>CASTOR OIL</td><td> 0,25</td><td>% ρφ</td><td>Excipient</td>
<td>Grade: Ew PfeUSP</td><td></td><td></td><td></td>
<td>ERITRITOL</td><td> 0,25</td><td>% ρ · ρ</td><td>Excipient</td>
<td>Grade: NFPhEur</td><td></td><td></td><td></td>
<td>LEVOCARNITINE</td><td> 0,25</td><td>“Ορρ</td><td>Excipient</td>
<td>Grade: PhEwüSP</td><td></td><td></td><td></td>
<td>(7] SODIUM HYDROXIDE</td><td> 7,3</td><td>ρΗ</td><td>PH adjustment</td>
<td>Grade: NFPhEw</td><td></td><td></td><td></td>
<td>(Sj WATER FOR INJECTION,</td><td>1Ó &</td><td>% p / p</td><td>QS setting</td>
PURIFIED WATER Grade: USP [i]? M * 1278-3, CRODA super refined polysortrate 80. Primary and lenitive Etausionate (2] Lenitive
Γ 5] Lenitive and tonicity agent [4] Stabilized oxychlor complex (Tip) Added by test value.
{5] Pemuies TR-2NF (Type C carbomer opolymer evaluated for Ph Ene). Secondary emulsifier (here lipophilic vehicle.
pjpH objective 7.3.
[5] Hydrophilic vehicle.
The formulation of Table I includes the concentrations of the assets and / or excipients as described above, which can be found in concentrations that vary with respect to what was set forth above. The variation may be such that the amounts are approximately those set forth above as long as it is determined that the amount is bioequivalent according to Lna
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INSTITUTO MEXICANO Di THE INDUSTRIAL PROPERTY
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regulatory agency such as the FDA (Agency for the Control of
Food and Medicines of the United States) or EMEA (European Medicines Agency).
The formulation can be preserved or not preserved (without Purite® content), such as a unit dose version. This version would be the same as in Table 1 except it would not contain Purite®.
Some embodiments of the invention are included in the following subsections:
1) A composition useful as an artificial tear, which is a salt-free emulsion that comprises castor oil and specifically excludes olive oil, and contains at least one active agent selected from the group consisting of polysorbate, carboxymethylcellulose and glycerin.
<td> 2)</td><td></td><td>The composition of</td><td>subsection 1 in which</td><td>the</td><td colspan="2">mixture</td>
<td colspan="2">understands</td><td>approximately</td><td>0.1% and 0.5% w / w of</td><td colspan="2">oil</td><td>from</td>
<td>castor</td><td></td><td></td><td></td><td></td><td></td><td></td>
<td> 3)</td><td></td><td>The composition of</td><td>subsections 1 - 2 in</td><td>the</td><td>that</td><td>he</td>
<td>oil</td><td>from</td><td>castor is the only one</td><td>oil in the emulsion.</td><td></td><td></td><td></td>
<td> 4)</td><td></td><td>The composition in</td><td>subsections 1 - 3 in</td><td>the</td><td>that</td><td>he</td>
<td>oil</td><td>from</td><td colspan="2">Castor is emulsified in an aqueous phase.</td><td></td><td></td><td></td>
<td> 5)</td><td></td><td>The composition of</td><td>subsection 4 in which the</td><td colspan="2">oil</td><td>from</td>
Castor is present in approximately 0.25% w / w.
6) The composition of subsections 4-5 which also include a primary and secondary emulsifier.
7)
The composition of the subsections
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MEXICAN INSTITUTE
OF INDUSTRIAL PROPERTY
<img file="MX355216B_D0021.tif" />
- 6 in which the composition contains a preservative.
8)
The composition of the subsection in which the conservative is selected from the group consisting of PURITE and benzalkonium chloride.
9)
The composition of the subsection in which the preservative is PURITE and is present in a concentration of approximately 0.01% w / v.
10) An emulsion for use in the dry eye treatment where the emulsion is free of salts and comprises castor oil, polysorbate 80, carboxymethyl cellulose and glycerin.
11) The composition of part 10 in which the emulsion also contains the emulsifier pemulin.
12) The emulsion of subsections 10-11 that also includes erythritol and levocarnitine.
13) An emulsion to treat dry eye, as shown in Table 1.
14) A method of treating dry eye comprising the administration of any of the compositions or emulsions of subsections 1-13.
15) A composition for treating dry eye or dry keratoconjunctivitis in which the composition comprises approximately 0.5% w / w Polysorbate 80, approximately
0.5% w / w carbomethylcellulose approximately
1.0% w / w glycerin, approximately 0.6% w / w boric acid, fVl1 1 fe
INSTITUTO MEXICANO Z. <- <sup>j:</sup> '/',
OF PROPERTY C ScxfiMflá 'INDUSTRIAL ^ ¾¾ .. - approximately 0.1% w / w pemulin approximately 0.25% w / w castor oil, approximately 0.25% w / w erythrole, approximately 0.25% w / w levocarnitine, hydroxide of sodium to adjust the pH to about
7.3 and water.
16). The composition in accordance with subsection 15 which further comprises 0.01% Purite®.
17) The composition of conformity with subsection 15 in which the composition is applied topically to an eye suffering from dry eye.
18) The composition in accordance with subsection 15 in which the composition is applied topically to an eye to relieve dry eye symptoms.
19) The composition in accordance with subsection 15 in which the composition is applied topically to an eye to avoid dry eye syndrome.
As used herein, the term "effective amount or effective dose" means an amount sufficient to achieve the desired result in the process or condition, and consequently will depend on the ingredient and the desired result. However, once the desired effect is known, determining the effective amount is within the skill of a person skilled in the art.
Formulation, composition and preparation as used herein are equivalent terms that refer to a composition of material suitable for use.
<td></td><td>IMPI MEXICAN INSTITUTE OF THE PROPERTY WDUSTRUL -----</td>
<td>pharmacist</td><td>(that is, to produce such a therapeutic effect</td>
<td>how to own</td><td>pharmacokinetic and toxicological properties</td>
acceptable).
The term prevent, as used herein, refers to a decrease in the appearance of dermatological symptoms (eg, hives rash) in a patient. The prevention can be complete (that is, without detectable symptoms) or partial, so that fewer symptoms are observed than would appear without treatment.
As used herein, the terms "prevent and treat" are not used with absolute significance. Treatment may refer to any delay in the onset, for example, a reduction in the frequency or severity of symptoms, improvement of symptoms, improvement of patient comfort, reduction of dry eye symptoms and the like. The effect of the treatment can be compared with an individual or group of individuals who do not receive a specific treatment, with the same patient before or after the suspension of treatment.
The term "therapeutically effective amount," as used herein, refers to the amount of composition or agent of a composition sufficient to improve one or more aspects of the disorder.
The therapeutic efficacy can also be expressed as a proportion of the increase or reduction. For example, a
IMPIAS
INSTITUTO MEXICANO Cl <sup>v</sup>
OF THE LINDUSTRIAL PROPERTY I Therapeutically effective amount may have at least 1.2 times, 1.5 times, 2 times, 5 times or more effect with respect to a control.
As used herein, includes any cure, improvement or prevention of a disease. Treatment can prevent the disease from occurring; inhibit the spread of the disease, alleviate the symptoms of the disease, totally or completely suppress the underlying cause of the disease, shorten the duration of the disease or achieve a combination of these. Treating or treating, as used herein (and as understood in the art), also broadly includes any approach to obtaining beneficial or desired results in the condition of a subject, including clinical results. Beneficial or desired clinical outcomes may include, by way of non-taxation, relief or improvement of one or more symptoms or conditions, reduction in the extent of a disease, stabilization (that is, no worsening) of the state of a disease, prevention of disease. transmission or expansion of a disease, delay or slowing of the progress of a disease, improvement or palliation of the state of a disease, reduction of disease recurrence and remission, either partial or total and either detectable or undetectable.
Treating and treatment, as used herein, may include prophylactic treatment. Treatment methods include administration to a subject of an asset.
therapeutically amount
WICKED
MEXICAN INSTITUTE
OF THE MKWIEDAD
INOUSTWAL 'effective of an agent
The administration stage may consist of a simple administration or may include a series of administrations. The duration of the treatment period depends on a variety of factors, such as the severity of the condition, the age of the patient, the concentration of the active agent, the activity of the compositions used in the treatment or a combination thereof. It will also be appreciated that the effective dosage of an agent used for the treatment or prophylaxis can be increased or reduced in the course of a specific prophylaxis treatment or regimen. Dosage changes can be obtained and become apparent by diagnostic tests known in the art. In some cases, chronic administration may be necessary. For example, the compositions are administered to the subject in an amount and for a duration sufficient to treat the patient.
DETAILED DESCRIPTION OF THE INVENTION
The administration of lipids to the human tear film to complete and enhance the natural lipid layer, often deficient due to a dysfunction of the Meibomian glands and other causes, is a recognized strategy for the treatment of dry eye signs and symptoms. . In theory, it is especially beneficial in cases of low humidity or when other internal / external factors increase
<img file="MX355216B_D0022.tif" />
IMPI
MEXICAN INSTITUTE
INDUSTRIAL PROPERTY evaporation of tear film. Ta emissive loss Ha water from the tear film causes an increase in salt content and causes hyperosmotic stress in the cells of the ocular surface.
The natural lipid layer is very thin and the total lipid volume is a small fraction of the total tear film volume. Improving the structure and function of the lipid layer by topically applying drops containing lipids only requires the administration of a small volume of oil; The excess of lipids will displace and alter the total aqueous volume, by far the main component of tears. It is also necessary that the lipids be administered rapidly, during a brief period of contact of a topical eye drop. Finally, the administered lipids must be established as part of the natural lipid layer, in the air interface.
The challenge of lipid release from an emulsion has been addressed through the use of substantial amounts of lipids (1-5%) and / or formulation of an easily separated emulsion system. The disadvantages of this approach include: the product requires agitation, the clarity of the emulsion is greatly reduced, the total volume of lipids administered to the eye is potentially large and variable and the tolerability may be less than for a drop for the eye completely watery
ΙΜΡΙ
MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY
<img file="MX355216B_D0023.tif" />
An alternative means of lipid release involves the use of a salt-sensitive emulsion system in a product intended for topical use that is largely salt-free. This system uses a surfactant and a polymer to increase viscosity to keep lipids (e.g. castor oil) in a stable submicron emulsion. When mixed with human tears, the natural salt content (often higher in the dry eye) is sufficient to quickly achieve a drop in the viscosity of the product due to the action of the polymeric structure. This loss of viscosity helps the release of lipids to a much greater degree and faster.
The efficiency in the administration of lipids can be defined as the amount of lipids released from the emulsion, as a proportion of the total lipid content, with respect to time under standard test conditions.
The efficiency of lipid administration in the presence of salt is maintained, for example, by the use of simple laboratory methods. Specifically, when diluted in water, this system exhibits a loss of viscosity proportional to the volume of water added. When exposed to salt (NaCl) by mixing 1: 1 with even a weak saline solution (30 mOsm), a loss of viscosity occurs
I over 60% compared to 50% when mixed with
INSTITUTO MEXICANO ¿5 * - <sub>;</sub>
INDUSTRIAL PROPERTY water. Higher salt intensity (up to approximately
600 mOsm) caused a considerably greater viscosity loss, which confirms the salt's action on the polymer structure.
Lipid release was demonstrated using a controlled centrifuge with an integrated real-time optical detector (Lumisizer). During 2 minutes of 4000 RPM of stress, the uniformity of the emulsion was confirmed by equivalent optical transmission from the bottom to the top product however, (volume
<td>of the</td><td>support of</td><td>sample</td><td>from</td><td>the centrifuge</td><td>for him</td>
<td>with</td><td>intensity</td><td>total and</td><td colspan="2">diluted in water</td><td>Without</td>
<td>the</td><td colspan="3">product dilution</td><td>with solution</td><td>saline</td>
<td colspan="2">and concentration</td><td>imitating</td><td>he</td><td>use in the eye)</td><td>exhibited</td>
a clear and remarkable change in product uniformity consistent with lipid release and migration to the top of the sample holder, consistent with flotation to the air interface. Surprisingly and beneficially, this can occur without coalescence (without increasing the size of the average lipid drop) allowing lipids to mix with the natural layer more effectively. The average particle (lipid droplet size) remained unchanged when the saline solution (Horiba) was added.
Clinical results confirmed that the new lipid emulsion system works effectively to prolong the
IMPIOS [NSTH'ITO Mexican Zc J ·
CE INDUSTRIAL PROPERTY '' l-LX —- TBUT (decomposition time also an increase in tolerability and tear) and demonstrates comfort with respect to an emulsion more optimized for drug administration.
The benefits of using a salt-sensitive emulsion system as shown in Table I, which is largely salt-free, include, but is not limited to:
1) There is no need to shake the product - excellent stability and uniformity inside the bottle;
2) Efficient administration of lipids to the eye due to the reduction in salt-induced viscosity and the destabilization of the emulsion structure that allows a more efficient lipid release;
3) Improved tolerability by decreasing the total lipid content;
<td> 4)</td><td>Stabilization</td><td>and effective complementation</td><td>of the</td>
<td>layer of</td><td>natural lipids;</td><td>Y</td><td></td>
<td> 5)</td><td>Possibly</td><td>greater administration of</td><td>lipids</td>
beneficial in patients with a higher salt content in tears, a vehicle called intelligent.
The incorporation of osmoprotectors (1-carnitine and erythritol) and humectants / lubricants (glycerin and carboxymethylcellulose increases the clinical usefulness of this product to a wider range of patients with dry eye than with other emulsion systems to treat lipid deficiency or dysfunction of the Meibomian gland.
IMPi
MEXICAN INSTITUTE> 2
OF THE PROPERTY CsnKjSL · »INDUSTRIAL
Example 1 - A study nnilt-inpnt-rn r · ^ ή rr.ra.Pi-. ·;
Hidden, randomized, 4-arm, parallel group to assess the safety, efficacy and acceptability of a single-dose eye drop formulation in subjects with dry eye disease
The objective of this study was to evaluate the safety, efficacy and acceptability of the formulation in Table 1, but without Purite®, called the next generation unit emulsion dose (NGE UD) in subjects with signs and symptoms of dry eye disease.
Methodology
This was a multicenter study, with a hidden, randomized, controlled active-ingredient, 4-arm investigator, with a parallel group designed to compare the safety, efficacy and acceptability of NGE UD with the unit dose of eye drops for sensitive lubricant-free eyes. ™ (OPTIVE UD) commercially available, NGE UD with a state-of-the-art Multiple Emulsion Dose (NGE MD. by its acronym in English) (the same formulation as in Table 1 but with Purite®) and NGE MD with a multiple dose of OPTIVE ™ lubricating eye drops (OPTIVE MD).
The planned duration of the study was 30 days for each subject and consisted of up to 3 scheduled visits (4 days 1 [initial value], 7 and 30 [departure]). Day 1, the subjects
<img file="MX355216B_D0024.tif" />
Suitable with signs and symptoms of dry eye disease were assigned according to a 2: 2: 1: 1 treatment allocation ratio to use NGE UD, OPTIVE UD, NGE MJp or OPTIVE MD, respectively. The randomization of the study was stratified by the initial Ocular Surface Disease Index® (OSDI) score (mild / moderate symptoms = score of 18 to 32; severe symptoms = score of> 32 to 65) . Approximately 300 subjects should participate in 13 to 14 locations in the United States in order to obtain 288 complete subjects assuming an abandonment rate of approximately 5%. Subjects were instructed to instill 1 to 2 drops of their assigned study product in each eye, as necessary, but at least 2 times a day for 30 days.
Number of subjects (planned and in participation)
It was planned that approximately 300 subjects would participate in this study. A total of 315 subjects participated.
Diagnosis and main selection criteria
Diagnosis / Subjects with signs and symptoms of dry eye disease
Key Inclusion Criteria:
Male or female subjects, at least 18 years old, with an initial OSDI score (day 1) of> 18 and <65 (based on a scale of 0 to 100) were selected to participate. The
<img file="MX355216B_D0025.tif" />
INSTITUTO MEXICANO Dlí THE INDUSTRIAL PROPERTY
<img file="MX355216B_D0026.tif" />
Subjects should have been using topical gout or o-í-ta lmoJráóg-igas for dry eye at least twice a day for at least 3 months before onset, on average. If it was a daily use of the RESTASIS® Cyclosporine Ophthalmic Emulsion, it should be in use for 6 months. It took three consecutive tests of decomposition time (TBUT) 10 seconds in at least 1 eye at the start. Using the modified National Eye Institute (NEI) chart, all subjects had to have at least a Grade 1 staining in at least 1 of the 5 areas of the cornea or in at least 1 of the 6 zones of the conjunctiva that relate to the dry eye in at least 1 eye at the beginning.
Key Exclusion Criteria:
The key exclusion criteria included a Schirmer test (with anesthesia) 2 mm in any eye at the beginning; Corneal or conjunctiva staining score of 5 (modified NEI table) at baseline in any of the 5 cornea zones or 6 conjunctiva zones in any eye; use of systemic medications that could affect a condition of dry eye or vision, unless the medication had been used in the same dose for at least 3 months before participating in the study and no dosage change was expected during the course of the study; history of surgery or trauma of the anterior segment example, cataract surgery, laser-assisted [LASIK, by photorefractive keratectomy or involving a
<img file="MX355216B_D0027.tif" />
MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY keratomileusis in situ limbo incision or prior to the start; and the current use of its acronym in English], any cornea) in and / or use in surgery that 12 months the 2 weeks prior to the start, and / or likelihood of use during the study period of any topical ophthalmic medication (for example , topical ophthalmologic spheroids, drops for glaucoma, any topical cyclosporine product other than Restasis®. Subjects who discontinued daily use of Restasis® less than 3 months before the start were excluded from the study.
Duration of treatment: The total duration of exposure to the study product (drops) for each subject was 30 days. The scheduling of visits consisted of a visit at the beginning (day 1) and 2 follow-up visits on days 7 (+ 3 days) and 30 / or early departure (+ 7 days).
Efficiency and safety measurements
Efficacy: Primary - OSDI questionnaire score
Secondary - TBUT (with fluorescein), corneal staining (modified NEI table, with fluorescein), conjunctiva staining (modified NEI table, with lysamine green) and Schirmer test (with anesthesia)
Others - Acceptability questionnaire and use questionnaire of the study product
<img file="MX355216B_D0028.tif" />
IM.PI6Ü3)
BMSrn'W? MEXICAN
IwuusraiAL PROPERTY
Security:
Biomicroscopy and visual acuity measurements at a distance.
Statistical Methods:
The population evaluable by intention to treat (ITT) consisted of randomized subjects in their entirety and was used for analysis of efficacy data based on randomized treatment. The safety population consisted of all treated subjects and was used for analysis of all safety data based on the treatment received. The population by protocol (PP) consisted of randomized subjects who did not present significant violations of the protocol, as determined before the
<td colspan="5">Database lock.</td><td rowspan="2">primary was</td><td rowspan="2">he</td><td rowspan="2">change in</td><td rowspan="2">he</td>
<td>The</td><td colspan="2">variable</td><td>from</td><td>effectiveness</td>
<td>score</td><td>from</td><td>OSDI</td><td>with</td><td>respect</td><td>to the initial</td><td>he</td><td>day 30 in</td><td>the</td>
ITT population. The primary efficacy analysis was carried out with the change with respect to the start of the OSDI score on day 30 through a 2-way analysis of the variance model (ANOVA) with treatment stratification and the initial OSDI as effects main.
The last observation extrapolation (LOCF) was used to impute lost data. Non-inferiority was assessed using an interval I of
IMPI
4ST1 MEXICAN INDUSTRIAL PROPERTY GUIDELINE
<img file="MX355216B_D0029.tif" />
confidence (CI) of 2 tails. The difference in treatment and 95% CI in the change with respect to the start in the OSDI score on day 30 between NGE UD and OPTIVE UD (NGE UD minus OPTIVE UD) was calculated based on the ANOVA model. The non-inferiority was established if the upper limit of the 95% CI was less than the prespecified margin of 7.3.
Secondary efficacy measurements included TBUT, corneal staining, conjunctiva staining and Schirmer's test. The gross values of these measurements were summarized for the ITT population, with the inclusion of lost data using the LOCF at each scheduled follow-up visit. The treatment difference and 95% CI were calculated for comparisons between treatments. The differences in treatment and 95% CI in the change with respect to the start in the OSDI score on day 30 between NGE UD and NGE MD and NGE MD and OPTIVE MD were also analyzed as secondary efficacy variables.
Acceptability was measured using the acceptability questionnaire and the use of the product was measured using the questionnaire on the use of the study product. Comparisons between groups were carried out using the ANOVA model with treatment and the initial OSDI stratification as the main effects.
The safety variables included adverse events,
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MEXICAN INSTITUTE
I heard L * MWMEDA »
IN.BUST8IAL
<img file="MX355216B_D0030.tif" />
Biomicroscopy and visual acuity at a distance. Since both eyes were treated, both eyes were included in the safety analyzes. The nomenclature of the Medical Dictionary for Regulatory Activities (MedDRA) was used to code for adverse events. The number and percentage of subjects with clinically significant biomicroscopy findings at one or more visits in any eye were placed on tables. The total frequency of distribution was analyzed using Pearson's chi-square test. To determine a clinically significant biomicroscopic discovery (increase of more than 1 degree of severity [worsening] with respect to the initial value) with an incidence rate of 5% in any treatment group, the mean severity and severity scores were summarized. severity distribution frequency at each scheduled visit.
The data of the eye with the worst severity in the scheduled visit were placed in tables. For distance visual acuity data.
The total number of letters read correctly was summarized according to the eye with the worst change with respect to the initial value at each scheduled visit.
The frequency of distribution was analyzed using Pearson's chi-square test.
A total of 315 subjects participated in the study and were included in the ITT population; 105 subjects in the group
NGE UD, 103 subjects in the OPTIVE UD group, 51 subjects in
<img file="MX355216B_D0031.tif" />
MEXICAN WSTITUTO
OF THE ÍÍ'ÍÍXtóTRML PROPERTY the group of NGE MD and 56 subjects in the group 'do QDTIVE MQ .. In general, 310 (98.4%) subjects in the ITT population completed the study. Of the subjects included in the population by protocol, 99.3% (303/305) completed the study while 98.4% (310/315) of the subjects in the safety population completed the study. A total of 384 subjects underwent selection, of which 69 subjects did not meet the selection requirements.
In the ITT population, the average age of all subjects was 54.8 years (standard deviation 14.33) with 83.2% (262/315) of the subjects in the age group> 40. In addition, 81.0% (255/315) of all subjects were women and 84.4% (266/315) were Caucasian.
Effectiveness:
• The reference value of primary efficacy was found. On day 30, no statistically significant difference was observed between the NGE UD and OPTIVE UD groups in the mean change with respect to the start in the OSDI score (95% confidence interval [-5.42, 2.51]), in the population ITT The NGE UD formulation was not inferior to the OPTIVE UD formulation in reducing the severity of dryness symptoms, as measured by the change with respect to the initial value in the OSDI score.
• Similar to the ITT population, there was no statistically significant difference between the groups of
IMPI
INSTITUTO MEXICANO I heard LA PROW.DAO NGE UD and OPTIVE UD of the PP population in the cattfeíRSM
<img file="MX355216B_D0032.tif" />
with respect to the initial value in the score 'al ·' · d * a, 3 0 »The · 95% confidence interval on the visit on day 30 was (5.72, 2.37); with an upper limit that is lower than the clinically relevant margin of 7.3.
• In the 4 treatment groups, there was a statistically significant difference (p <0.001) in the mean change with respect to the initial value in the OSDI score on visits on day 7 and day 30 for the ITT and PP populations.
• The NGE UD group was not inferior to the NGE MD group in the average change with respect to the initial value in the OSDI score on day 30.
• The NGE UD group was not inferior to the OPTIVE UD and NGE MD groups in secondary efficacy measurements of TBUT, cornea staining, conjunctiva staining and Schirmer test.
• In general, there were no statistically significant differences between the NGE UD and OPTIVE UD groups, the NGE UD and NGE MD groups or the NGE MD and OPTIVE MD groups, in the mean values for each question of the acceptability questionnaire during the day visits 7 and on day 30 (except in question 5 in the comparison of NGE MD with respect to OPTIVE MD on day 7 and in the comparison of NGE UD with respect to NGE MD on day 30), and in the average number of times per day that the study product was used during the week prior to visits on day 7 and day 30.
<img file="MX355216B_D0033.tif" />
<img file="MX355216B_D0034.tif" />
Security:
• At least 1 emergent adverse treatment event (TEAE) for any cause was reported in 11.4%, 15.5%, 13.7% and 10.7% of the subjects in the NGE UD, OPTIVE UD, NGE MD and OPTIVE MD, respectively.
• No deaths were recorded in this study. Two serious adverse events (stone in the bile duct [NGE UD group] and ankle fracture [OPTIVE MD group]) were reported, none of which was related to the treatment in the opinion of the investigator.
In general, 3 subjects dropped out due to adverse events, 1 subject in each of the NGE UD groups,
NGE MD and OPTIVE MD.
• TEAE related to treatment were reported in 4.8%, 8.7%, 7.8% and 5.4% in subjects in the NGE UD, OPTIVE UD, NGE MD and OPTIVE MD groups, respectively. The most common adverse events related to treatment (preferred terms) in the treatment groups were pain at the site of instillation and blurred vision; NGE UD (3.8%, 2.9%), OPTIVE UD (3.9%, 2.9%), NGE MD (3.9%, 0.0%) and OPTIVE MD (3.6%, 1.8%).
• In most subjects, no change in visual acuity was observed at a distance on day 30 for the 4 treatment groups.
IMPI
INSTITUTO MEXICANO Di IZ LNDUmtAL PROPERTY
<img file="MX355216B_D0035.tif" />
Conclusions, .........
Efficacy: The results of this study demonstrate that the NGE UD formulation is not inferior to the OPTIVE UD formulation in reducing the severity of dryness in subjects with mild to severe dry eyes.
Safety: NGE UD seemed to be well tolerated during the study. The most commonly reported adverse events related to treatment were pain at the site of instillation and blurred vision. Throughout the study, there were no serious adverse events related to the treatment. The safety profile was consistent with that of OPTIVE UD, OPTIVE MD and NGE MD. This supports the safety of the NGE UD formulation in clinical use and confirms the safety of the NGE MD formulation.
It is noted that in relation to this date, the best method known by the applicant to implement said invention is that which is clear from the present description of the invention.
kf
Contents32
35 sheets
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69 members in 30 offices
Priority claims14
| Document | Office | Kind | Date |
|---|---|---|---|
| 201161568089 | United States of America | P | |
| 201161568089 | United States of America | P | |
| 61568089 | United States of America | – | |
| 201261625401 | United States of America | P | |
| 201261625401 | United States of America | P | |
| 61625401 | United States of America | – | |
| 2012068615 | United States of America | W | |
| 2012068615 | United States of America | W | |
| 61568089 | – | – | – |
| 61625401 | – | – | – |
| PCTUS2012068615 | – | – | – |
| US201161568089P | – | – | – |
| US201261625401P | – | – | – |
| WO2012US68615 | – | – | – |
Members69
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|---|---|---|---|
| CA2858574A1 | Canada | A1 | |
| US2013150324A1 | United States of America | A1 | |
| WO2013086438A1 | World Intellectual Property Organization (WIPO) | A1 | |
| WO2013086449A1 | World Intellectual Property Organization (WIPO) | A1 | |
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| MX2014006804A | Mexico | A | |
| PH12014501296A1 | Philippines | A1 | |
| EP2787968A1 | European Patent Office (EPO) | A1 | |
| EP2787969A1 | European Patent Office (EPO) | A1 | |
| CN104114152A | China | A | |
| CL2014001518A1 | Chile | A1 | |
| JP2015504860A | Japan | A | |
| HK1201458A | Hong Kong, China | A | |
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| RU2018119362A3 | Russian Federation | A3 | |
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1 legal event, as the office reported them to INPADOC
Events
| Event | Code | |
|---|---|---|
| Grant or registrationFG | FG |
Numbers
- Publication
- 355216
- Publication, DOCDB
- 355216
- Publication, EPODOC
- MX355216
- Application
- 2014006804
- Application, DOCDB
- 2014006804
- Application, EPODOC
- MX20140006804
Titles2
- Spanish
- ADMINISTRACIÓN EFICIENTE DE LIPIDOS A LA PELICULA LAGRIMAL HUMANA MEDIANTE EL USO DE UN SISTEMA DE EMULSIÓN SENSIBLE A LA SAL.
- English
- EFFICIENT LIPID DELIVERY TO HUMAN TEAR FILM USING A SALT-SENSITIVE EMULSION SYSTEM.
Classification
- CPC, 13
- A61K47/26
- A61K47/32
- A61K9/0048
- A61K9/107
- A61K31/047
- A61K31/341
- A61K31/717
- A61P27/02
- A61P27/04
- A61K47/38
- A61K47/10
- A61K47/02
- A61K47/44
- IPC, 6
- A61K31 047
- A61K9 00
- A61K9 107
- A61K31 341
- A61K31 717
- A61K47 32