U.S. patent application number 14/388447 was filed with the patent office on 2015-05-28 for semi-solid topical composition which contains pirfenidone and modified diallyl disulphide oxide (m-ddo) for eliminating or preventing acne.
The applicant listed for this patent is CELL THERAPY AND TECHNOLOGY S.A. DE C.V.. Invention is credited to Juan Socorro Armendariz Borunda, Jose Agustin Rogelio Magana Castro, Pedro Pena Santoyo, Laura Vazquez Cervantes.
Application Number | 20150148382 14/388447 |
Document ID | / |
Family ID | 48096131 |
Filed Date | 2015-05-28 |
United States Patent
Application |
20150148382 |
Kind Code |
A1 |
Armendariz Borunda; Juan Socorro ;
et al. |
May 28, 2015 |
SEMI-SOLID TOPICAL COMPOSITION WHICH CONTAINS PIRFENIDONE AND
MODIFIED DIALLYL DISULPHIDE OXIDE (M-DDO) FOR ELIMINATING OR
PREVENTING ACNE
Abstract
The instant invention relates to a semi-solid topical
composition containing Pirfenidone and an antimicrobial/antiseptic
agent such as Modified Diallyl Disulfide Oxide (M-DDO) and its
preparation process, offering advantages compared to other
pharmaceutical forms of topical administration known in the state
of the art, useful as antifibrotic, anti-inflammatory and
antiseptic agent in the prevention, treatment and reversion of acne
and post acne lesions. Said compositions is also useful for
reducing skin redness, detaining the formation of new acne
outbreaks, reversing already existing outbreaks and regenerating
skin damage caused by acne.
Inventors: |
Armendariz Borunda; Juan
Socorro; (Mexico, MX) ; Magana Castro; Jose Agustin
Rogelio; (Mexico, MX) ; Pena Santoyo; Pedro;
(Mexico, MX) ; Vazquez Cervantes; Laura; (Mexico,
MX) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
CELL THERAPY AND TECHNOLOGY S.A. DE C.V. |
Mexico, D.F. |
|
MX |
|
|
Family ID: |
48096131 |
Appl. No.: |
14/388447 |
Filed: |
February 27, 2013 |
PCT Filed: |
February 27, 2013 |
PCT NO: |
PCT/MX2013/000027 |
371 Date: |
February 5, 2015 |
Current U.S.
Class: |
514/345 |
Current CPC
Class: |
A61K 31/4418 20130101;
A61P 17/10 20180101; A61K 31/351 20130101; A61P 17/02 20180101;
A61K 9/0014 20130101; A61P 17/00 20180101; A61K 9/06 20130101; A61K
31/4412 20130101; A61K 31/4418 20130101; A61K 2300/00 20130101;
A61K 31/351 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/345 |
International
Class: |
A61K 31/4412 20060101
A61K031/4412; A61K 9/00 20060101 A61K009/00; A61K 31/351 20060101
A61K031/351 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 28, 2012 |
MX |
MX/A/2012/003694 |
Claims
1. A semi-solid topical composition for eliminating, reducing or
preventing skin acne occurrence, comprising 2%, 4%, 6%, 8% or 10%
in weight of pirfenidone, 0.016% in weight of Modified Diallyl
Disulfide Oxide (M-DDO), and 91.984% in weight of a gelling agent
and other excipients or additives.
2. The semi-solid topical composition according to claim 1,
comprising 8% in weight of pirfenidone, 0.016% in weight of
Modified Diallyl Disulfide Oxide (M-DDO) and 91.984% in weight a
gelling agent and other excipients or additives.
3. The semi-solid topical composition according to claim 1, wherein
the gelling agent is selected from the group consisting of
methylcellulose, hydroxypropylcellulose, sodium
carboxymethylcellulose, polyvinyl alcohol, polyvinylpirrolidone,
carboxyvinyl polymers, carbomer and acrylic polymers.
4. The semi-solid topical composition according to claim 3, wherein
the gelling agent is carbomer.
5. The semi-solid topical composition according to claim 1, wherein
the excipients or additives are selected from the group consisting
of propylene glycol as solubilizer, macrogol-glycerol
hydroxystearate as non-ionic solubilizer and triethanolamine as
neutralizing agent.
6. The semi-solid topical composition according to claim 1, wherein
the Modified Diallyl Disulfide Oxide (M-DDO) acts as an
antimicrobial and antiseptic agent.
7. The semi-solid topical composition according to claim 1, wherein
said composition is in gel, cream or ointment form.
8. The semi-solid topical composition according to claim 1, having
a pH of 5 to 6.4.
9. The semi-solid topical composition according to claim 1, for
preventing chronic inflammation caused by acne.
10. The semisolid topical composition according to claim 1, for
reducing skin redness.
11. The semi-solid topical composition according to claim 1, for
preventing new acne outbreaks.
12. The semi-solid topical composition according to claim 1, for
reversing existing outbreaks.
13. The semi-solid topical composition according to claim 1, for
regenerating skin damage caused by acne.
14. The semi-solid topical composition according to claim 1, for
avoiding or removing acne scars.
15-16. (canceled)
17. A method for eliminating, reducing or preventing acne,
comprising administering a semi-solid topical composition according
to claim 1 to the skin of a person in need thereof.
18. A method for avoiding chronic inflammation caused by acne,
reducing skin redness, preventing new acne outbreaks, reversing
existing outbreaks, regenerating skin damage caused by acne and/or
avoiding and removing post-acne scars, comprising administering a
semi-solid topical composition according to claim 1 to the skin of
a person in need thereof.
19. A process for manufacturing a semi-solid topical composition
containing Pirfenidone and Modified Diallyl Disulfide Oxide
(M-DDO), wherein the process comprises the following stages: 1.-In
a container, place 90% of the total water and add: Carbomer (1 g)
Leave till complete moisturizing. (IDENTIFY MIXTURE "A") 2.-In
another container, place and heat at 40.degree. C. (IDENTIFY
SOLUTION "A") Propylene glycol (50 g) Add slowly, under constant
stirring till complete dissolution, maintaining at 40.degree. C.
1-phenyl-5-methyl-2-(1H)-pyridone (8 g) Add slowly and under
constant stirring, maintaining at 40.degree. C. Macrogol-glycerol
Hydroxystearate (13 g) Add under constant stirring, maintaining at
40.degree. C. Modified Diallyl Disulfide Oxide (M-DDO) (0.8 g)
3.-In another container, place 10% of the total water and under
constant stirring add: Triethanolamine (1 g) Stir till
homogenization (IDENTIFY SOLUTION "B") 4.-Add to the container
(step 1), one by one, under constant stirring till homogenization
each time and in the indicated order. SOLUTION "A" SOLUTION "B"
5.-Sample and analyze the topical composition.
Description
FIELD OF THE INVENTION
[0001] The invention relates to a semi-solid topical composition
containing 8% Pirfenidone and 0.016% Modified Diallyl Disulfide
Oxide (M-DDO) acting synergically for eliminating or preventing the
occurrence of various forms of skin acne and as antimicrobial and
antiseptic agent.
BACKGROUND OF THE INVENTION
[0002] Acne is an inflammatory disease of the pilosebaceous
follicles associated to alterations of keratinization and
seborrhea; it is characterized by the formation of skin lesions
such as comedones, papules, pustules, cysts, and abscesses,
frequently leaving residual scars.
[0003] The acne is doubtless the most frequent skin disease
worldwide; it has traditionally been considered that two main
factors are involved in acne occurrence, the exaggerated production
of sebum and abnormal desquamation of epidermal cells finally
causing an excessive keratinization, but recent studies have added
genetic predisposition and inflammation as acne-causing factors.
According to recent statistical data, it is estimated that about
85% of people between 11 and years of age suffer from acne, i.e.
about 20 million people are affected in Mexico alone. The incidence
data show a maximum peak at the age of 18, followed by a
progressive reduction which is more prominent after the age of 30;
however, between 25 and 35% of adults older than 35 years of age
show occasional acne exacerbations.
[0004] Because many factors are involved, the cause of acne is not
precisely known. However the genetic background combined with
endocrine, inflammatory and infectious factors are the ones
involved in the polymorphic characteristics of acne.
[0005] Five main primary pathogenic factors interact in a complex
way to cause acne lesions, i.e.:
1. Genetic predisposition. 2. Excessive production of sebum by the
sebaceous glands. 3. Alterations of the keratinization process with
abnormal desquamation of the sebaceous follicular epithelium
(causing comedogenesis). 4. Proliferation of Propionibacterium
acnes. 5. Release of skin inflammatory mediators, namely TNF-alpha
and IL-1 alpha.
Genetic Factors
[0006] The genetic predisposition is not mediated through a simple
Mendelian character, but is caused by a polygenic mechanism
originating from the special receptivity of the pilosebaceous
follicle to respond more intensively to androgens, in a fashion
different from the way healthy people respond. This phenomenon is
possibly caused by a major activity and concentration of the
5-alpha-reductase present in the sebaceous glands. In patients with
acne, it is frequent to find a family background with this entity,
even the same clinical type and same identity.
Sebum Production Factor
[0007] Several studies conducted regarding sebum function in acne,
have shown that the sebaceous lipids are regulated by peroxisome
proliferation activated-receptors (PPAR) and by sterol
transcription factors.
[0008] The PPAR nuclear receptors act together with retinoids X
receptors (RXR), to regulate epidermis growth and differentiation
as well as lipids metabolism. Sterol transcription factors regulate
the increase in the formation of sebaceous lipids induced by the
insulin-like growth factor (IGF-1).
[0009] Other researches regarding the function of the sebaceous
gland have contributed to offer information about the essential
function of these glands in skin functions regulation. The
sebaceous gland has direct and indirect antibacterial activities.
Sapienic acid, a sebum lipid, has an innate antimicrobial activity
and is increased by the activation of Toll-like receptor 2 (TLR-2)
through contact with skin bacteria. Moreover, the sebaceous gland
produces antibacterial peptides and pro-inflammatory cytokines that
are induced in the sebocytes due to the presence of bacteria. The
sebaceous gland acts as an endocrine organ that responds to
androgen and hormone changes and is the control center for a
complex program regulating neuropeptides that act as the
hypothalamus-hypophysis-adrenal axis. This function of the
sebaceous gland is influenced mainly by the corticotropin-releasing
hormone, the protein binding to it, and by the corticotropin
receptors. The corticotrophin-releasing hormone levels change in
response to stress and its function as regulator of the sebaceous
gland is to act as a brain-skin connection explaining the
relationship between stress and skin inflammatory disorders,
especially atopic dermatitis and acne. Moreover, it has been
reported that ectopeptidase receptors such as dipeptidyl peptidase
IV and aminopeptidase-N play an important part in the regulation of
sebocytes.
[0010] Other researchers have shown, in a cell line derived from
human keratinocytes, that sebum lipid peroxidation can activate
inflammatory mediators, including interleukin-6 (IL-6) and
lipoxygenase. The oxidized squalene can also stimulate
keratinocytes proliferation behavior, suggesting that this lipid
could be partially responsible for comedone formation. It has also
been shown that lipoperoxides have a proinflammatory effect on the
sebaceous follicle. Lipoperoxides produce leukotriene 4, a powerful
chemoattractant recruiting neutrophils and macrophages and
stimulating the production of pro-inflammatory cytokines.
Endocrine Factors
[0011] Androgens are hormones synthesized in the testicles, ovaries
and suprarenal cortex. During puberty, through mechanisms which are
little known, the hypophysis starts secreting larger quantities of
luteinizing hormones (LH) and follicle-stimulating hormones (FSH)
that, together, are responsible for increasing testicular growth,
spermatogenesis and steroidogenesis. Testosterone acts on the
sebaceous glands, increasing their size and sebum synthesis. In
women, the mechanism is similar, and the luteinizing hormone acts
on the ovaries increasing testosterone synthesis and secretion.
Through skin biopsies of the face of patients with acne, it has
been observed that sebaceous glands are larger and more lobulated
during puberty, precisely the stage during which there is an
increase in the levels of the mentioned hormones. The conclusion is
that acne is induced by androgens, but only because of a genetic
predisposition that causes alteration in androgens normal
metabolism at pilosebaceous follicle level, with an increase in the
concentration and activity of 5-alpha-reductase, present in the
sebaceous glands of the affected parts.
Infectious Factors
[0012] In the past, it was believed that acne was only an
infectious process caused by the bacteria "Acne bacillus". Then the
function of bacteria in acne pathogenesis was questioned after said
organism, now called Propionibacterium acnes was isolated from
control subject not affected by acne.
[0013] There is little qualitative difference between acne patients
and acne-free control patients when microbiological studies are
conducted. The skin flora in both groups is essentially a triad
including Propionibacterium acnes, and Staphylococcus epidermis and
a yeast that can be Pityrosporum ovale or Pityrosporum
orbiculare.
[0014] Despite the above, the possible association between bacteria
and acne pathogenesis was reinforced because of well documented
findings of clinical improvement in acne patients treated with
systemic antibiotics. The antibacterial therapy does not affect P.
obliculare or P. ovale because they are on the upper part of the
acrofundibulum of the sebaceous follicle. The anaerobic P. acnes,
on the other hand, appear to play a central part in the development
of inflammation in acne. Maybe the most convincing evidence is the
demonstration that the antibiotic therapy leads to a significant
suppression of P. acnes which is accompanied by a reduction in the
number of inflammatory lesions.
[0015] Propionibacterium acnes and Staphylococcus epidermis produce
a lipase that hydrolizes serum triglycerides in free fatty acids
that are powerful irritating agents of the follicular canal, when
they are applied to the skin or injected intradermally, causing
inflammation and comedones.
[0016] It has also to be stated that Propionibacterium acnes
activates the complement system alternatively, and this has led to
postulate that this infectious mechanism could play an important
part in the production of acne inflammatory lesions.
Keratinization Factor
[0017] During puberty, in response to the larger quantities of
androgens produced at this stage, the sebaceous glands that were
previously relatively inactive increase in size and become more
lobulated, augmenting sebum production that is poured outside; this
explains the first acne sign: seborrhea. The recently synthesized
sebum contains triglycerides, squalene and wax esters and it is
known that Propionibacterium acnes and Staphylococcus epidermis
through a lipase hydrolyze the triglycerides of this sebaceous
material, converting them into free fatty acids that together with
other irritating substances such as squalene and oleic acid, cause
an inflammation of the follicular canal that, in turn, responds to
the inflammation with hyperkeratosis. The resulting corneal
material falls into the follicle lumen forming, together with the
excessive sebum, a plug that distends the follicle walls. This
follicle, unable to excrete the material, produces further
inflammation, causing the first and most important acne elemental
lesion: comedone, provoking the dilatation of the follicular hole
through the pressure exerted by the plug in its attempt to be
expulsed.
Inflammatory Factors
[0018] Several studies have focused on the function of inflammatory
mediators, as well as on the interrelation of these factors with
sebaceous lipids and matrix metalloproteinases (MMP's) in acne
physiopathology.
[0019] One of the pioneer researches in this field was carried out
by Jeremy et al in 2003 who studied the initial events of acne
lesions and found that the immunological changes and inflammatory
responses occur before keratinocytes hyperproliferations with a
pattern similar to a delayed type IV hypersensitivity response.
[0020] The immune response is mediated through CD4+ lymphocytes and
macrophages. These researchers propose as explanation that the
subsequent production of cytokines activates local endothelial
cells and induces an exacerbated regulation of inflammatory
vascular markers (E-selectin, vascular cell adhesion molecule-1
[VCAM-1], intracellular adhesion molecule 1 [ICAM-1], and the human
leukocyte antigen DR [HLA-DR]) in the vasculature around the
pilosebaceous follicle.
[0021] An important fact is that all the process is initiated by
the exacerbated regulation of IL1-.beta. that has a proinflammatory
action in response to the relative deficiency of linoleic acid
caused by the excess of sebum and the perturbation of the barrier
function within the follicle.
[0022] More than a decade ago, in an in vitro study, Vowels et al
demonstrated the presence of a soluble factor of P. acnes that also
induces the production of proinflammatory cytokines in cellular
lines derived from human monocytes. This product of P. acnes
induces the synthesis of the Tumor Necrosis Factor alpha
(TNF-.alpha.) and interleukin 1-beta (IL1-.beta.) in said cellular
lines.
[0023] It was also shown that cytokines induction by P. acnes
occurred through the activation of "TOLL-LIKE-2" (TLR-2) receptor
that triggers said inflammatory responses. Said transmembrane
protein has a cytoplasmic portion homologous to the interleukin 1
(IL-1) receptor, and can thus trigger the signaling cascade
activating the nuclear transcriptional factor Kappa-B
(NF-k.beta.).
[0024] NF-k.beta. is a key transcription factor regulating the
transcription of genes codifying for the production of
proinflammatory proteins such as TNF-.alpha., Interleukin 1 (IL-1)
and Interleukin-6 (IL-6).
[0025] The activation of other transcriptional factors, AP-1
(Activator Protein-1) induces MMP's genes, the proteic products of
which degrade and alter the dermal matrix.
[0026] Other recent studies have shown that this chain of events
occurs in inflammatory lesions of patients with facial acne. It has
been shown that Propionibacterium acnes also induces Toll-type
receptors. This is additional evidence that the inflammatory
cytokines acting through autocrine and paracrine mechanisms amplify
their corresponding receptors and amplify the signaling route
activating the Activator Protein 1 (AP-1) that is a transcription
factor.
[0027] Further, it has been shown that the liberation of the same
transduction signals does not only stimulate proinflammatory
cytokines but also stimulates enzymes production in the fibroblast,
said enzymes denominated MP's are the proteins responsible for
extracellular matrix degradation, causing imperfect repair of the
chronic inflammatory acne lesions and finally leading to skin
sequelae that manifest themselves as filling defects commonly known
as "ice-picks lesions" or "pockmarks". FIG. 2 shows the molecular
chain for the production of said dermal sequelae.
[0028] In FIG. 3, the transmission system, at cellular level, of
signals intervening in acne and finally triggering the inflammatory
process in which Toll-type receptors intervene to activate the
nuclear factor NF-k.beta. that causes the production of
TNF-.alpha., IL-1, IL-6 and other proinflammatory cytokines is
shown. Thus, also through this type of receptors, AP-1 is
activated, which is a transcription factor that will finally
activate MMP's, enzymes involved in the formation of post-acne
scars and deficiencies in the production of extracellular
matrix.
[0029] In acne treatment, the use of antimicrobial agents is usual
among physicians, because clinically there is an improvement in
acne patients when this type of products is used, due to the
potentiating factor of P. acnes in the metabolism of sebum causing
an irritating effect that will generate further inflammation in the
patient.
[0030] The combination of two elements, Pirfenidone and M-DDO, the
final objective of which is the symptomatological management of
acne and its sequelae, has shown to be highly effective in the
treatment of acne patients at different lesion stages, from light
to severe, showing an improvement with regard to severity, number
and duration of lesions, that are the main objectives for the acne
physician.
[0031] In short, it can be said that acne shows a complex
interaction of many factors creating a complex problem where some
key points are confluent with genetic factors and inflammation,
such as:
1. Inflammatory events precede hyper keratinization. 2. P. acnes
contributes to the inflammation through the activation of Toll-like
receptors in the inflammatory cell membranes. 3. Sebum production
is partially regulated by PPAR receptors. 4. The sebaceous gland is
a neuroendocrine-inflammatory organ that coordinates and executes a
local response to the stress and to normal functions. 5. Androgenes
influence follicular cells. 6. Oxided lipids in sebum can stimulate
the production of inflammatory mediators. 7. Matrix
metalloproteinases (MMP's) are present in sebum and their number
diminishes as the lesions are treated.
OBJECTIVE OF THE INVENTION
[0032] The main objective of the instant invention is to offer
semi-solid topical compositions for eliminating, reducing or
preventing the occurrence of skin acne, comprising preferably a
composition of 8% in weight of
pirfenidone[1-phenyl-5-methyl-2-(1H)-pyridone] and M-DDO at a
concentration of 0.016%, a gelling agent and one or more excipients
or additives.
[0033] Another object of the instant invention is the use of M-DDO
as antimicrobial and antiseptic agent eliminating the need for
using other preservative agents in the composition. Moreover, the
objective of the instant invention is a treatment method and/or the
application or pharmaceutical use of a semisolid topical
composition containing pirfenidone and M-DDO for eliminating,
reducing or preventing acne. Moreover, said semi-solid topical
composition acts to prevent chronic inflammation caused by acne,
reduces skin redness, detains the formation of new acne outbreaks,
reverts the already existing outbreaks, regenerates acne-related
skin damage and prevents and removes post-acne scars.
[0034] Other objectives of the instant invention relate to the
pharmaceutical presentation of the topical composition in gel,
cream or ointment form.
[0035] An additional objective is the manufacturing process of the
semi-solid topical composition containing pirfenidone and M-DDO for
eliminating, reducing or preventing acne.
[0036] The above objectives illustrate the instant invention but do
not limit it; besides, its applications and/or pharmaceutical uses
are shown in the preparation of drugs for eliminating, reducing or
preventing acne.
BRIEF DESCRIPTION OF THE FIGURES
[0037] Other characteristics and advantages of the instant
invention shall be obvious from the following detailed description
of the objects and preferred embodiments, of the attached claims
and of the drawings and figures accompanying them, wherein:
[0038] FIG. 1 shows M-DDO chemical formula.
[0039] FIG. 2 shows the molecular chain of dermal sequelae.
[0040] FIG. 3 shows the signal transmission system, at cellular
level, intervening in acne and that finally triggers the
inflammatory process.
[0041] FIGS. 4-15 clearly show the therapeutic effects of the
semi-solid topical composition of pirfenidone containing M-DDO for
eliminating or preventing acne in 12 patients with different acne
types.
DETAILED DESCRIPTION OF THE INVENTION
[0042] The instant invention relates to a semi-solid topical
composition in the form of a gel, cream or ointment comprising
[1-phenyl-5-methyl-2-(1H)-pyridone] preferably at 8%, a gelling
agent, cellulose derivatives, polyacrylic reticulated acid polymers
and carboxyvinylic derivatives; and other additives such as
triethanolamine as neutralizing agent, propylene glycol as
solubilizer, macrogol-glycerol hydroxystearate as non-ionic
solubilizer, among other commonly used additives in gel
preparation. Moreover, the semi-solid topical composition contains
0.016% weight/volume of an antimicrobial and antiseptic agent such
as M-DDO. [1-phenyl-5-methyl-2-(1H)-pyridone) is a drug that has
been used in the restoration of tissues showing fibrotic lesions
and for preventing fibrotic lesions. This compound, called
Pirfenidone, is per se a known compound and its pharmacological
effects have been described, for example, in Japanese applications
KOKAI numbers 87677/1974 and 1284338/1976, as anti-inflammatory
agent having antipyretic and analgesic effects. U.S. Pat. No.
3,839,346, published on Oct. 1, 1974, U.S. Pat. No. 3,974,281,
published on Aug. 10, 1978, U.S. Pat. No. 4,042,699, published Aug.
16, 1977, and U.S. Pat. No. 4,052,509, published on Oct. 4, 1977,
describe methods for obtaining pirfenidone, as well as its use as
anti-inflammatory agent. Mexican patent 182,266 describes the
anti-fibrotic activity of
Pirfenidone[1-phenyl-5-methyl-2-(1H)-pyridone].
##STR00001##
[0043] C.sub.12H.sub.11ON
[0044] MW=185
[0045] Name: 1-phenyl-5-methyl-2-(1H)-pyridone.
[0046] The combination of Pirfenidone and M-DDO generates a
semi-solid composition for swift prevention, control and
elimination of skin problems caused by acne. It acts as
anti-inflammatory and antimicrobial agent due to its dual action
mechanism, because, besides blocking pro-inflammatory
cytokines--especially TNF-.alpha. ((Tumor Necrosis Factor-alpha)-,
it also shows antimicrobial and antiseptic action. It thus acts on
two of the main causes of acne.
[0047] Thus, the semi-solid topical composition of Pirfenidone and
M-DDO: [0048] Has a direct effect blocking TNF-.alpha., TGF-.beta.
and other proinflammatory cytokines; [0049] Through its MMP's
modulating action, it helps prevent scar sequelae; [0050] It has an
effect on KGF, modulating keratinocytes production; [0051] It has a
potent anti oxidant effect, helping the metabolism of sebaceous
gland and blocking the inflammatory stimulation of P. acnes.
[0052] Upon reducing the inflammation it opens gland ducts and thus
inhibits anaerobic bacterial growth.
[0053] Moreover, the results shown in FIGS. 4 to 15 clearly
evidence that patients with acne outbreak respond excellently to
the treatment with the semi-solid topical composition object of the
instant invention when it is applied two or three times a day. In
most of the patients, obvious improvements are obtained in less
than a month, when it is applied on a daily basis.
[0054] The series of FIGS. 4-15 clearly show the potent action of
Pirfenidone and M-DDO on acne and the sequelae caused by said
disease.
[0055] The semi-solid topical composition acts as a biomodulator of
the serum concentrations of inflammatory proteins and thus has an
anti-TNF-alpha and anti IL-6 action, and acts directly on acne
inflammatory factor; moreover, through its antimicrobial effect, it
acts on the bacteria Propionibacterium acnes.
[0056] The semi-solid topical composition permits that the
pharmacological properties of pirfenidone and M-DDO acts
synergically on the skin, and thus the selection of a gelling agent
is extremely important. The gelling agents were thus selected from
the group consisting of: methylcellulose, hydroxypropylcellulose,
sodium carboxymethylcellulose, polyvinyl alcohol,
polyvinylpirrolidone, carboxyvinyl polymer, carbomer, acrylic
polymers. Said gelling agents are used together with additives for
obtaining a pH ranging from 5 to 6.4, at which level said gelling
agents show a higher viscosity. Said composition also comprises
M-DDO, propylene glycol, macrogol-glycerol hydroxystearate and
triethanolamine.
[0057] Thus, the semi-solid topical composition of the instant
invention reduces or prevents skin acne and comprises preferably 8%
in weight of the composition of Pirfenidone and to 95% in weight of
the composition of a gelling agent selected from the group
consisting of methylcellulose, hydroxypropylcellulose, sodium
carboxymethylcellulose, polyvinyl alcohol, polyvinylpirrolidone,
carboxyvinyl polymers, carbomer, acrylic polymers; and one or
several additives selected from propylene glycol, macrogol,
-glycerol, hydroxystearate, besides M-DDO.
[0058] Thus, the semi-solid topical composition is also effective
for preventing chronic inflammation caused by acne, for reducing
skin redness, for detaining the formation of new acne outbreaks,
for reverting the already existing outbreaks, for regenerating skin
damage caused by acne and for preventing and removing past acne
scars.
Preparation Process
[0059] The semi-solid topical composition containing Pirfenidone
and M-DDO is prepared following a process comprising the following
stages:
1.-In a container, place 90% of the total water and add: [0060]
Carbomer (1 g) [0061] Leave till complete moisturizing. (IDENTIFY
MIXTURE "A") 2.-In another container, place and heat at 40.degree.
C. (IDENTIFY SOLUTION "A") [0062] Propylene glycol (50 g) [0063]
Add slowly, under constant stirring till complete dissolution,
maintaining at 40.degree. C. [0064]
1-phenyl-5-methyl-2-(1H)-pyridone (8 g) [0065] Add slowly and under
constant stirring, maintaining at 40.degree. C. [0066]
Macrogol-glycerol Hydroxystearate (13 g) [0067] Add under constant
stirring, maintaining at 40.degree. C. [0068] Modified Diallyl
Disulfide Oxide (M-DDO) (0.8 g) 3.-In another container, place 10%
of the total water and under constant stirring add: [0069]
Triethanolamine (1 g) [0070] Stir till homogenization (IDENTIFY
SOLUTION "B") 4.-Add to the container (step 1), one by one, under
constant stirring till homogenization each time and in the
indicated order. [0071] SOLUTION "A" [0072] SOLUTION "B" 5.-Sample
and analyze the topical composition.
Pirfenidone and M-DDO Composition
[0073] The composition of 0.016% Pirfenidone and M-DDO described in
the instant invention permits the obtainment of a gel, cream or
ointment containing contact antimicrobial/antiseptic agent, that
are stable, biodegradable, and non-toxic having a wide action
spectrum not only against gram negative and gram positive
microorganisms but also against fungi.
[0074] FIG. 1 shows the formula of Modified Diallyl Disulfide
Dioxide [M-DDO], the chemical name of which is
[1,2-diallyl-1-(5-methyl-tetrahydro-2H-pyran-2-yloxy)disulfonium]+6-[(ben-
zyl, methyl, octylammonium)
(hydroxymethylamin)(methylamin)]-tetrahydro-2H-pyran-3-oxy]
chloride:
##STR00002##
[0075]
{[1,2-diallyl-1-(5-methyl-tetrahydro-2H-pyran-2-yloxy)disulfonium]+-
6-[(benzyl, methyl, octylammonium)
(hydroxymethylamin)(methylamin)]-tetrahydro-2H-pyran-3-oxy]}
[0076] C.sub.35H.sub.62O.sub.5N.sub.3S.sub.2Cl
[0077] Molecular weight=703.5
[0078] Tables 1, 2, 3 and 4 (shown hereinafter) present the
information obtained after conducting microbiological tests, also
known as antimicrobial challenge, of M-DDO against various
bacteria, showing its powerful anti-bacterial capacity. Moreover,
Table 5 (shown hereinafter) presents the results of M-DDO against
Propionibacterium acnes. Moreover, said table also shows that the
combination of Pirfenidone and M-DDO (semi-solid topical
composition containing Pirfenidone and M-DDO) results in a highly
effective removal of P. acnes in a matter of seconds.
[0079] [Pirfenidone and ODD-M] contains Modified Diallyl Disulfide
Oxide (M-DDO), this active substance has been identified, before
its chemical modification as Allicin, substance coming from a plant
the scientific name of which is Allium sativum, having the original
formula:
##STR00003##
[0080] C.sub.6H.sub.10OS.sub.2
[0081] Molecular Weight=162
[0082] Name: Diallyl-Disulfide Oxide
[0083] The use of natural substances in the treatment of various
diseases--including diseases of infectious etiology--constitutes
currently a challenge for modern medicine. In 1994, Cavallito et
al. isolated and identified the active compound of Allium sativum
extracts which they denominated Allicin and in 1947 they
synthesized Diallyl Disulfide Oxide (Allicin) but unfortunately
could not prepare a stable molecule from it because of its
continuous loss of efficacy in a very short period of time. Between
2000 and 2005, a group of Mexican researchers could stabilize
diallyl Disulfide oxide, adding a cofactor that does not modify the
allicin antimicrobial action or other actions but grants it a long
term action, obtaining thus a stable, biodegradable, non-toxic and
large spectrum action contact antimicrobial/antiseptic agent, not
only against gram negative and gram positive microorganisms but
also against fungi.
[0084] The following antimicrobial action mechanisms of M-DDO in
this topical composition [Pirfenidone and M-DDO] have been
proposed: [0085] 1. Various chemical reactions of M-DDO sulphydric
radicals on microbial metabolism, causing mainly the enzymatic
inhibition of 11 enzymes of the microorganism either inserting
sulfur radicals or causing protein modifications in the enzymes,
and inhibiting thus metabolic actions of the microorganism, causing
its death. [0086] 2. The creation of free radicals (ROS), through
Redox reactions, that break the microorganism cell wall through
oxidative stress, upon "sequestering" the oxygen serving as union
between the chains of NAG (n-Acetyl-glucosamine acid) and NAM
(N-Acetyl muramic acid), weakening the microorganism wall, causing
its rupture and thus the death of the microorganism. [0087] 3. The
inhibition of the microorganism protein unfolding, through the
inhibition of the RNA polymerase enzyme, which is a
sulfur-dependent enzyme. [0088] 4. Metal metabolism alteration in
the microorganism, causing also metabolic alterations in said
microorganism.
Antimicrobial Challenges
[0089] Various antimicrobial challenges have been studied in
various institutions in order to evaluate the efficacy of M-DDO
[Pirfenidone and M-DDO] against the most frequent microorganisms
susceptible to develop resistance and against some microorganisms
that may cause grater problem with regard to their eradication
because of spore production.
[0090] The initial challenges are conducted with collection
microorganisms universally requested for evidencing the efficacy of
a product. The challenges performed in our laboratory show that
with a 30 second contact, more than 100.00% of the microorganisms
were eliminated, including Candida albicans. Studies conducted at
the Universidad Nacional Autonoma de Mexico resulted in a 99.999%
elimination of the microbial charge. Moreover, results of studies
conducted by a company authorized by the authorities to perform
challenge studies show results that are similar to the results
obtained in the test conducted at UNAM, UAEM and in our laboratory
(Grupo Medifarma)(Tables 1, 2 and 3).
TABLE-US-00001 TABLE 1 Microbial challenge studies conducted at
Grupo Medifarma TEST CONTACT TIME MICROORGANISM 30 seconds
Escherichia coli 100% ATCC 10536 Escherichia coli 100% ATCC 11229
Pseudomonas aeruginosa 100% ATCC 9027 Kliebsiella pneumoniae 100%
ATCC 10031 Proteus vulgaris 100% ATCC 6380 Staphylococcus aureus
100% ATCC 6538 Staphylococcus epidermidis 100% ATCC 12228 Candida
albicans 100% ATCC 10231
TABLE-US-00002 TABLE 2 Microbial challenge studies conducted at
UNAM TEST CONTACT TIME MICROORGANISM 30 seconds Escherichia coli
99.999% ATCC 11229 Staphylococcus aureus 99.999% ATCC 6538
Salmonella typhi 99.999% CA-C001
TABLE-US-00003 TABLE 3 Microbial challenge studies conducted at
ARj. TEST CONTACT TIME MICROORGANISM 30 seconds Escherichia coli
99.999% ATCC 11229 Staphylococcus aureus 99.999% ATCC 6538
Pseudomonas aeruginosa 99.999% ATCC 15442-2 Kliebsiella pneumoniae
100% ATCC 10031 Candida albicans 100% ATCC 10231
[0091] A second type of challenges were performed at the
Universidad Autonoma del Estado de Morelos with microorganisms
collected from hospitalized patients and thus said microorganisms
had already been in contact with antimicrobial agents and could
show resistance (Table 4).
TABLE-US-00004 TABLE 4 Studies conducted at the Universidad
Autonoma del Estado de Morelos TEST CONTACT TIME MICROORGANISM 30
seconds Escherichia coli 99.961% Staphylococcus aureus 99.999%
Shigella flexnieri 99.999% Enterobacter cloacae 100% Serratia
marcenses 100% Salmonella typhi 99.170% Enterobacter faecalis
99.972% Salmonella enteritidis 100%
TABLE-US-00005 TABLE 5 Antimicrobial action of Pirfenidone and
M-DDO gel. Exposition Percentage of reduction Product Time of
bacteria viability (%) M-DDO 0.016% 30 sec 99.999 M-DDO 0.016% 60
sec 99.999 M-DDO 0.016% 15 min 100 Pirfenidone and M-DDO 30 sec 98
Pirfenidone and M-DDO 60 sec 98.18 Pirfenidone and M-DDO 15 min
99.902
[0092] The result of these challenges with microorganisms isolated
from hospitalized patients was a reduction of at least 99.17% of
the microbial charge in only 30 second contact with M-DDO.
Examples
[0093] A semi-solid topical composition containing preferably 8
grams of pirfenidone, 0.016 grams of M-DDO, 92 grams of excipient,
was prepared for the treatment of patients with various grades of
acne affectation; the results of said application are shown
hereinafter:
[0094] A group of 70 patients with moderate to severe acne, were
classified depending on severity grade and the number of
inflammatory and non inflammatory lesions, the number of papules,
pustules, nodes, open or closed comedones, according to the
criteria shown in Table 6.
TABLE-US-00006 TABLE 6 Grade* Description 0 Clean skin without
inflammatory or non-inflammatory lesions 1 Nearly clean skin; few
non-inflammatory lesions and no more than two inflammatory lesions
2 Medium severity; higher than Grade 1; some non- inflammatory
lesions, a few inflammatory lesions (only papules/pustules; without
node lesions) 3 Moderate severity; higher than Grade 2; many non-
inflammatory lesions and various inflammatory lesions, but no more
than two node lesions 4 Severe; higher than Grade 3; many
inflammatory and non-inflammatory lesions; and a few node lesions
*Acne classification scale according to the FDA
TABLE-US-00007 TABLE 7 Distribution of the test group: Number of
Grade Patients % 0 0 0 1 14 20 2 33 47.1 3 19 27.2 4 4 5.7 Total 70
100
[0095] The number of lesions for each patient was counted according
to the grade of the subject. The resulting data are shown in Table
8, where a reduction averaging nearly 50% with regard to
inflammatory lesions after 28 days of treatment can be
observed.
TABLE-US-00008 TABLE 8 Number of Inflammatory Lesions Day Grade Day
0 7 days 14 days 21 days 28 days 1 8 +/- 2 6 +/- 3 5 +/- 2 3 +/- 2
2 +/- 2 2 24 +/- 8 19 +/- 8 15 +/- 5 12 +/- 4 10 +/- 4 3 62 +/- 8
48 +/- 6 42 +/- 7 37 +/- 5 33 +/- 5 4 120 +/- 15 102 +/- 14 88 +/-
16 76 +/- 13 65 +/- 15
[0096] The results show that the topical composition of the instant
invention permits to obtain an efficacious treatment of acne. These
results are comparable to the results obtained with other acne
conventional treatments. However, the treatment according to the
instant invention is clearly better compared to the pre-existing
methods.
TABLE-US-00009 TABLE 9 shows an example of semi-solid topical
composition. COMPONENT QUANTITY (g) % PIRFENIDONE 8.0 8.0 VISCOSITY
AGENT (Carbomer) 1.0 1.0 SOLUBILIZER (Propylene glycol) 50.0 50.0
NON-IONIC SOLUBILIZER(Macrogol- 13.0 13.0 glycerol Hydroxystearate)
ANTIMICROBIAL, ANTISEPTIC AGENT 0.8 0.016 (Allicin modified:
diallyl disulfide oxide) 2% NEUTRALIZING AGENT (Triethanolamine)
1.0 1.0 PURIFIED WATER Q.S. 100.0 26.984
TABLE-US-00010 TABLE 10 shows an example of a semi-solid topical
composition containing 2% Pirfenidone. COMPONENT QUANTITY (g) %
PIRFENIDONE 2.0 2.0 VISCOSITY AGENT (Carbomer) 1.0 1.0 SOLUBILIZER
(Propylene glycol) 12.5 50.0 NON-IONIC SOLUBILIZER (Macrogol- 3.2
13.0 glycerol Hydroxystearate) ANTIMICROBIAL, ANTISEPTIC AGENT 0.8
0.016 (Allicin modified diallyl disulfide oxide) 2% NEUTRALIZING
AGENT 1.0 1.0 (Triethanolamine) PURIFIED WATER Q.S. 100.0
32.984
TABLE-US-00011 TABLE 11 shows an example of a semi-solid topical
composition containing 4% Pirfenidone. COMPONENT QUANTITY (g) %
PIRFENIDONE 4.0 4.0 VISCOSITY AGENT (Carbomer) 1.0 1.0 SOLUBILIZER
(Propylene glycol) 25.0 50.0 NON-IONIC SOLUBILIZER (Macrogol- 6.4
13.0 glycerol Hydroxystearate) ANTIMICROBIAL, ANTISEPTIC AGENT 0.8
0.016 (Allicin modified diallyl disulfide oxide) 2% NEUTRALIZING
AGENT 1.0 1.0 (Triethanolamine) PURIFIED WATER Q.S. 100.0
30.984
TABLE-US-00012 TABLE 12 shows an example of a semi-solid topical
composition containing 6% Pirfenidone. COMPONENT QUANTITY (g) %
PIRFENIDONE 6.0 6.0 VISCOSITY AGENT (Carbomer) 1.0 1.0 SOLUBILIZER
(Propylene glycol) 50.0 50.0 NON-IONIC SOLUBILIZER (Macrogol- 13.0
13.0 glycerol Hydroxystearate) ANTIMICROBIAL, ANTISEPTIC AGENT 0.8
0.016 (Allicin modified diallyl disulfide oxide) 2% NEUTRALIZING
AGENT 1.0 1.0 (Triethanolamine) PURIFIED WATER Q.S. 100.0
28.984
TABLE-US-00013 TABLE 13 shows an example of a semi-solid topical
composition containing 10% Pirfenidone. COMPONENT QUANTITY (g) %
PIRFENIDONE 10.0 10.0 VISCOSITY AGENT (Carbomer) 1.0 1.0
SOLUBILIZER (Propylene glycol) 50.0 50.0 NON-IONIC SOLUBILIZER
(Macrogol- 13.0 13.0 glycerol Hydroxystearate) ANTIMICROBIAL,
ANTISEPTIC AGENT 0.8 0.016 (Allicin modified diallyl disulfide
oxide) 2% NEUTRALIZING AGENT 1.0 1.0 (Triethanolamine) PURIFIED
WATER Q.S. 100.0 24.984
[0097] These compositions are illustrative but not limitative
examples of the scope of the instant invention.
[0098] Table 14 shows the definitions of the "acronyms" indicated
in FIG. 3.
TABLE-US-00014 TABLE 14 RTT1 Toll-like Receptor 1 RTT2 Toll-like
Receptor 2 RTT4 Toll-like Receptor 4 RTT6 Toll-like Receptor 6 MD-2
Molecule that associates with the extra cellular portion of TLR4
CD14 CD14 Receptor Myd88 Myeloid Differentiation Factor 88 IRAK
IL-1 Receptor Associated Kinase TRAF-6 TNF receptor associated
factor 6 MAPK Mitosis activated protein kinase NF-k.beta. Nuclear
Factor Kappa-Beta LPS Lipopolysaccharide TIR Toll/interleukin
receptor AP-1 Activator protein 1 IRF 3 Interferon regulatory
protein 3 IRF7 Interferon regulatory protein 7 TAK1 Activated
Kinase 1 TRIF Toll Factor/IL-1R TBK1 TANK binding kinase 1 TRAM
TRIF related adaptor molecule IFN Interferon
* * * * *